EP1925303A2 - Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure - Google Patents

Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure Download PDF

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Publication number
EP1925303A2
EP1925303A2 EP08004265A EP08004265A EP1925303A2 EP 1925303 A2 EP1925303 A2 EP 1925303A2 EP 08004265 A EP08004265 A EP 08004265A EP 08004265 A EP08004265 A EP 08004265A EP 1925303 A2 EP1925303 A2 EP 1925303A2
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Prior art keywords
prevention
pharmaceutically acceptable
antagonist
acceptable salt
angiotensin
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EP08004265A
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German (de)
French (fr)
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EP1925303B1 (en
EP1925303A3 (en
Inventor
Bernward Schoelkens
Norbert Bender
Badrudin Rangoonwala
Gilles Dagenais
Hetzel Gerstein
Anders Ljunggren
Salim Yusuf
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Sanofi Aventis Deutschland GmbH
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Sanofi Aventis Deutschland GmbH
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Priority to SI200031084T priority Critical patent/SI1925303T1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to use of an inhibitor of the renin-angiotensin system (RAS) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of stroke, diabetes and /or congestive heart failure (CHF).
  • RAS renin-angiotensin system
  • CHF congestive heart failure
  • the present invention further relates to a method of prevention and/or treatment of stroke, diabetes and/or CHF, comprising administering a therapeutically effective amount of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof to a patient in need of such prevention and/or treatment.
  • RAS cardiovascular diseases, particularly arterial hypertension and heart failure.
  • the RAS can be interferred with by inhibition of the enzymes synthesizing angiotensins or by blocking the corresponding receptors at the effector sites.
  • Available today are inhibitors of the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT II) antagonists.
  • ACE angiotensin converting enzyme
  • AT II angiotensin II type 1 receptor
  • ACE inhibitors are compounds which inhibit the conversion of angiotensin I into the active angiotensin II as well as the breakdown of the active vasodilator bradykinin. Both of these mechanisms lead to vasodilation. Such compounds have been described in, for example, EP 158927 , EP 317878 , US 4,743,450 , and US 4,857,520 .
  • Ramipril (disclosed in EP-A-079022 ) is a long-acting ACE inhibitor. Its active metabolite is the free diacid ramiprilat, which is obtained in vivo upon administration of ramipril. In hypertensive patients administration of ramipril is known to cause a reduction in peripheral arterial resistance and thus a reduction of the blood pressure without a compensatory rise in heart rate. It is currently being used in the treatment of hypertension and CHF. Furthermore, ramipril has been shown to reduce mortality in patients with clinical signs of congestive heart failure after surviving an acute myocardial infarction. Ramipril has been suggested to have an added advantage over many other ACE inhibitors due to its pronounced inhibition of ACE in tissues resulting in organ protective effects in e.g. the heart, kidney, and blood vessels.
  • Compounds that interfere with the RAS including ACE inhibitors and AT II antagonists are currently used in the treatment of various cardiovascular disorders, especially in patients exhibiting a high blood pressure. Use of said compounds in prevention of cardiovascular disorders is much less common and the use of said compounds in the prevention of stroke, diabetes and /or CHF is hitherto unknown.
  • the present invention relates to use of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of stroke, especially in patients exhibiting normal or low blood pressure.
  • the present invention further relates to use of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of diabetes.
  • the present invention also relates to use of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of development of CHF in patients with no preexisting CHF, i.e. no signs or symptoms of CHF.
  • Another aspect of the invention is a method of prevention of stroke, diabetes and/or CHF, comprising administering a therapeutically effective amount of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof, to a patient in need of such prevention.
  • Yet another aspect of the invention is a pharmaceutical formulation for use in the prevention of stroke, diabetes and/or CHF, comprising a therapeutically effective amount of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof.
  • a further aspect of the invention is the use of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof, in the prevention of stroke, diabetes and/or CHF, by administering the inhibitor of the RAS or a pharmaceutically acceptable derivative thereof, to a patient in need of such prevention.
  • cardiovascular and metabolic disorders such as stroke, diabetes and CHF can be prevented by use of an inhibitor of RAS, particularly an ACE inhibitor that interferes with the synthesis of angiotensin II.
  • RAS cardiovascular and metabolic disorders
  • the present invention is especially surprising in that especially patients with an essentially maintained heart function and/or exhibiting a normal or low blood pressure benefit markedly from the preventive action of the inhibitors of RAS.
  • the invention describes a new method to prevent disorders such as stroke, diabetes and/or CHF by administration of an inhibitor of the RAS.
  • stroke includes both fatal and non-fatal.
  • diabetes include both type I diabetes, also known as insulin-dependent, diabetes mellitus (IDMM), and type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM).
  • IDMM insulin-dependent, diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • inhibitor of the renin-angiotensin system includes any compound which in itself or upon administration blocks the negative effects of angiotensin II on the vasculature either by reducing the synthesis of angiotensin II or blocking its effect at the receptor.
  • angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable derivative thereof includes any compound which in itself or upon administration interferes with the synthesis of angiotensin II.
  • the present invention includes the mixture of isomers as well as the individual stereoisomers.
  • the present invention further includes geometrical isomers, rotational isomers, enantiomers, racemates and diastereomers.
  • the inhibitors of RAS may be used in neutral form, e.g. as a carboxylic acid, or in the form of a salt, preferably a pharmaceutically acceptable salt such as the sodium, potassium, ammonium, calcium or magnesium salt of the compound at issue.
  • a pharmaceutically acceptable salt such as the sodium, potassium, ammonium, calcium or magnesium salt of the compound at issue.
  • the compounds listed above can be used in hydrolyzable ester form.
  • the inhibitors of the RAS include all prodrugs thereof, whether active or inactive in vitro.
  • protected derivatives may not possess pharmacological activity per se, they may be administered e.g. parenterally or orally, and thereafter metabolized in vivo to form pharmacologically active inhibitors of RAS.
  • Preferred examples are ramipril, which is metabolized into ramiprilat, and candesartan cilexetil, which is metabolized into candesartan.
  • Inhibitors of the RAS include ACE inhibitors, AT II antagonists, also known as angiotensin receptor blockers (ARBs), renin antagonists, and vasopeptidase inhibitors (VPls).
  • ACE inhibitors include ACE inhibitors, AT II antagonists, also known as angiotensin receptor blockers (ARBs), renin antagonists, and vasopeptidase inhibitors (VPls).
  • ARBs angiotensin receptor blockers
  • renin antagonists also known as renin antagonists
  • VPls vasopeptidase inhibitors
  • vasopeptidase inhibitors embraces so-called NEP/ACE inhibitors (also referred to as selective or dual acting neutral endopeptidase inhibitors) which possess neutral endopeptidase (NEP) inhibitory activity and angiotensin converting enzyme (ACE) inhibitory activity.
  • NEP neutral endopeptidase
  • ACE angiotensin converting enzyme
  • renin antagonists embraces renin inhibitors.
  • the RAS inhibitors may exhibit a long term duration, medium term duration or short term duration.
  • ACE inhibitors or pharmaceutically acceptable derivatives thereof, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF include, but is not limited to, the following compounds:
  • Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors for uses in the present invention are ramipril and ramiprilat. Information about ramipril and ramiprilat can be obtained e.g. from the Merck Index., 12th ed., 1996, pp. 1394-1395 .
  • AT II antagonists or pharmaceutically acceptable derivatives thereof, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF include, but is not limited to, those described in European Patent Applications, Publication Nos. 253310 , 323841 , 324377 , 399731 , 400974 , 401030 , 403158 , 403159 , 407102 , 407342 , 409332 , 411507 , 411766 , 412594 , 412848 , 415886 , 419048 , 420237 , 424317 , 425211 , 425921 , 426021 , 427463 , 429257 , 430300 , 430709 , 432737 , 434038 , 434249 , 435827 , 437103 , 438869 , 442473 , 443568 , 443983 , 445811 , 446062 , 449699 , 450566 , 453210 ,
  • Preferred AT II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention include, but is not limited to, compounds with the following generic names: candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan.
  • AT II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention are candesartan and candesartan cilexetil.
  • Candesartan and candesartan cilexetil are known from European Patent No. 459 136 B1 , US 5,196,444 and US 5,703,110 to Takeda Chemical Industries.
  • Candesartan cilexetil is currently manufactured and sold world-wide by AstraZeneca and Takeda.e.g. under the trade names Atacand ® , Amias ® and Blopress ® .
  • NEP/ACE-inhibitors or pharmaceutically acceptable derivatives thereof, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF include, but is not limited to, those compounds disclosed in U.S. Patents Nos. 5,508,272 , 5,362,727 , 5,366,973 , 5,225,401 , 4,722,810 , 5,223,516 , 5,552,397 , 4,749,688 , 5,504,080 , 5,612,359 , 5,525,723 , 5,430,145 , and 5,679,671 , and European Patent Applications 0481522 , 0534263 , 0534396 , 0534492 and 0671172 .
  • NEP/ACE inhibitors for use in the present invention are those which are designated as preferred in the above U.S. patents and European Patent Applications and are incorporarted herein by reference. Especially preferrred is the NEP/ACE inhibitor omapatrilat (disclosed in U.S. Patent No. 5,508,272 ), or MDL100240 (disclosed in U.S. Patent No. 5,430,145 ).
  • Renin-inhibitors or pharmaceutically acceptable derivatives thereof, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF include, but is not limited to, the following compounds:
  • the present invention relates to pharmaceutical formulations comprising as active ingredient an RAS inhibitor or a pharmaceutically acceptable derivative or prodrug thereof, including metabolites, for use in the prevention of stroke, diabetes and/or conge-stive heart failure (CHF).
  • RAS inhibitor or a pharmaceutically acceptable derivative or prodrug thereof, including metabolites, for use in the prevention of stroke, diabetes and/or conge-stive heart failure (CHF).
  • CHF conge-stive heart failure
  • the RAS inhibitor is formulated into a pharmaceutical formulation for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or some other mode of administration.
  • the pharmaceutical formulation may contain the inhibitor in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • the active ingredient may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • solid, powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • the active ingredient may be separately premixed with the other, non-active ingredients, before being mixed to form a formulation.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active ingredient of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
  • Hard gelatine capsules may contain granules of the active ingredients.
  • Hard gelatine capsules may also contain the active ingredients in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder to be recon-stituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent before use.
  • the total amount of active ingredient suitably lies in the range of from about 0.1 % (w/w) to about 95 % (w/w) of the formulation, suitably from 0.5 % to 50 % (w/w) and preferably from 1 % to 25 % (w/w).
  • the pharmaceutical formulations may contain between about 0.1 mg and about 1000 mg of active ingredient, preferably between 1 mg and 100 mg of active ingredient.
  • the dose of the active ingredient to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician.
  • the dosage will suitably be in the range of from about 0.01 mg/kg to about 20 mg/kg, preferably between 0.1 mg/kg and 10 mg/kg.
  • the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
  • dosages, and especially oral and parenteral dosages will be in the range of from about 0.1 to about 100 mg per day of active ingredient, preferably between 1 and 50 mg per day of active ingredient.
  • the systolic blood pressure at inclusion of the patients was on average 138 mm Hg and thus the patients were normotensive at study start. After one month of therapy with either ramipril or placebo, the systolic blood pressure had decreased by 5.48 mm Hg and 1.59 mm Hg, respectively.
  • MI myocardial infarction
  • CV cardiovascular

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Abstract

The present invention relates to use of an inhibitor of the renin-angiotensin system (RAS) or a pharmaceutically acceptable derivative thereof, particularly ramipril or ramiprilat, in the manufacture of a medicament for the prevention of stroke, diabetes and /or congestive heart failure (CHF). The present invention further relates to a method of prevention and/or treatment of stroke, diabetes and/or CHF, comprising administering a therapeutically effective amount of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof, particularly ramipril or ramiprilat, to a patient in need of such prevention and/or treatment.

Description

    FIELD OF INVENTION
  • The present invention relates to use of an inhibitor of the renin-angiotensin system (RAS) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of stroke, diabetes and /or congestive heart failure (CHF). The present invention further relates to a method of prevention and/or treatment of stroke, diabetes and/or CHF, comprising administering a therapeutically effective amount of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof to a patient in need of such prevention and/or treatment.
    • BACKGROUND OF THE INVENTION
  • Compounds that interfere with the RAS are well known in the art and are used to treat cardiovascular diseases, particularly arterial hypertension and heart failure. Principally, the RAS can be interferred with by inhibition of the enzymes synthesizing angiotensins or by blocking the corresponding receptors at the effector sites. Available today are inhibitors of the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT II) antagonists.
  • ACE inhibitors are compounds which inhibit the conversion of angiotensin I into the active angiotensin II as well as the breakdown of the active vasodilator bradykinin. Both of these mechanisms lead to vasodilation. Such compounds have been described in, for example, EP 158927 , EP 317878 , US 4,743,450 , and US 4,857,520 .
  • Ramipril (disclosed in EP-A-079022 ) is a long-acting ACE inhibitor. Its active metabolite is the free diacid ramiprilat, which is obtained in vivo upon administration of ramipril. In hypertensive patients administration of ramipril is known to cause a reduction in peripheral arterial resistance and thus a reduction of the blood pressure without a compensatory rise in heart rate. It is currently being used in the treatment of hypertension and CHF. Furthermore, ramipril has been shown to reduce mortality in patients with clinical signs of congestive heart failure after surviving an acute myocardial infarction. Ramipril has been suggested to have an added advantage over many other ACE inhibitors due to its pronounced inhibition of ACE in tissues resulting in organ protective effects in e.g. the heart, kidney, and blood vessels.
  • Compounds that interfere with the RAS including ACE inhibitors and AT II antagonists are currently used in the treatment of various cardiovascular disorders, especially in patients exhibiting a high blood pressure. Use of said compounds in prevention of cardiovascular disorders is much less common and the use of said compounds in the prevention of stroke, diabetes and /or CHF is hitherto unknown.
    • SUMMARY OF THE INVENTION
  • The present invention relates to use of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of stroke, especially in patients exhibiting normal or low blood pressure.
  • The present invention further relates to use of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of diabetes.
  • The present invention also relates to use of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the prevention of development of CHF in patients with no preexisting CHF, i.e. no signs or symptoms of CHF.
  • Another aspect of the invention is a method of prevention of stroke, diabetes and/or CHF, comprising administering a therapeutically effective amount of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof, to a patient in need of such prevention.
  • Yet another aspect of the invention is a pharmaceutical formulation for use in the prevention of stroke, diabetes and/or CHF, comprising a therapeutically effective amount of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof.
  • A further aspect of the invention is the use of an inhibitor of the RAS or a pharmaceutically acceptable derivative thereof, in the prevention of stroke, diabetes and/or CHF, by administering the inhibitor of the RAS or a pharmaceutically acceptable derivative thereof, to a patient in need of such prevention.
    • DETAILED DESCRIPTION OF THE INVENTION
  • It has surprisingly been found that cardiovascular and metabolic disorders such as stroke, diabetes and CHF can be prevented by use of an inhibitor of RAS, particularly an ACE inhibitor that interferes with the synthesis of angiotensin II. The present invention is especially surprising in that especially patients with an essentially maintained heart function and/or exhibiting a normal or low blood pressure benefit markedly from the preventive action of the inhibitors of RAS. The invention describes a new method to prevent disorders such as stroke, diabetes and/or CHF by administration of an inhibitor of the RAS.
  • Patients exhibiting a normal or low blood pressure are known as normotensive patients. Examples of guidelines defining blood pressure values for different patient groups including different ages, include guidelines issued by the WHO and JNC (USA). In the present invention, a suitable definition of a normal or low blood pressure can be found in JNC VI, which is hereby incorporated by reference.
  • In the present invention, "stroke" includes both fatal and non-fatal.
  • In the present invention, "diabetes" include both type I diabetes, also known as insulin-dependent, diabetes mellitus (IDMM), and type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM).
  • In the present invention, "inhibitor of the renin-angiotensin system (RAS) or a pharmaceutically acceptable derivative thereof" includes any compound which in itself or upon administration blocks the negative effects of angiotensin II on the vasculature either by reducing the synthesis of angiotensin II or blocking its effect at the receptor.
  • In the present invention, "angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable derivative thereof" includes any compound which in itself or upon administration interferes with the synthesis of angiotensin II.
  • When the inhibitor of the RAS used in the present invention have several asymetric carbon atoms, they can consequently exist in several stereochemical forms. The present invention includes the mixture of isomers as well as the individual stereoisomers. The present invention further includes geometrical isomers, rotational isomers, enantiomers, racemates and diastereomers.
  • Where applicable, the inhibitors of RAS may be used in neutral form, e.g. as a carboxylic acid, or in the form of a salt, preferably a pharmaceutically acceptable salt such as the sodium, potassium, ammonium, calcium or magnesium salt of the compound at issue. Where applicable the compounds listed above can be used in hydrolyzable ester form.
  • In the present invention, the inhibitors of the RAS include all prodrugs thereof, whether active or inactive in vitro. Thus, although such protected derivatives may not possess pharmacological activity per se, they may be administered e.g. parenterally or orally, and thereafter metabolized in vivo to form pharmacologically active inhibitors of RAS. Preferred examples are ramipril, which is metabolized into ramiprilat, and candesartan cilexetil, which is metabolized into candesartan.
  • Inhibitors of the RAS include ACE inhibitors, AT II antagonists, also known as angiotensin receptor blockers (ARBs), renin antagonists, and vasopeptidase inhibitors (VPls).
  • The phrase "vasopeptidase inhibitors" embraces so-called NEP/ACE inhibitors (also referred to as selective or dual acting neutral endopeptidase inhibitors) which possess neutral endopeptidase (NEP) inhibitory activity and angiotensin converting enzyme (ACE) inhibitory activity.
  • The phrase "renin antagonists" embraces renin inhibitors.
  • In the present invention, the RAS inhibitors may exhibit a long term duration, medium term duration or short term duration.
  • ACE inhibitors or pharmaceutically acceptable derivatives thereof, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF include, but is not limited to, the following compounds:
    • alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat, enapril, epicaptopril, foroxymithine, fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril, lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril, muracein A, muracein B, muracein C, pentopril, perindopril, perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride, quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride, spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocapril hydrochloride, teprotide, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril and zofenoprilat.
  • Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors for uses in the present invention are ramipril and ramiprilat. Information about ramipril and ramiprilat can be obtained e.g. from the Merck Index., 12th ed., 1996, pp. 1394-1395.
  • AT II antagonists or pharmaceutically acceptable derivatives thereof, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF include, but is not limited to, those described in European Patent Applications, Publication Nos. 253310 , 323841 , 324377 , 399731 , 400974 , 401030 , 403158 , 403159 , 407102 , 407342 , 409332 , 411507 , 411766 , 412594 , 412848 , 415886 , 419048 , 420237 , 424317 , 425211 , 425921 , 426021 , 427463 , 429257 , 430300 , 430709 , 432737 , 434038 , 434249 , 435827 , 437103 , 438869 , 442473 , 443568 , 443983 , 445811 , 446062 , 449699 , 450566 , 453210 , 454511 , 454831 , 456442 , 456442 , 456510 , 459136 , 461039 , 461040 , 465323 , 465368 , 467207 , 467715 , 468372 , 468470 , 470543 , 475206 , 475898 , 479479 , 480204 , 480659 , 481448 , 481614 , 483683 , 485929 , 487252 , 487745 , 488532 , 490587 , 490820 , 492105 , 497121 , 497150 , 497516 , 498721 , 498722 , 498723 , 499414 , 499415 , 499416 , 500297 , 500409 , 501269 , 501892 , 502314 , 502575 , 502725 , 503162 , 503785 , 503838 , 504888 , 505098 , 505111 , 505893 , 505954 , 507594 , 508393 , 508445 , 508723 , 510812 , 510813 , 511767 , 511791 , 512675 , 512676 , 512870 , 513533 , 513979 , 514192 , 514193 , 514197 , 514198 , 514216 , 514217 , 515265 , 515357 , 515535 , 515546 , 515548 , 516392 , 517357 , 517812 , 518033 , 518931 , 520423 , 520723 , 520724 , 521768 , 522038 , 523141 , 526001 , 527534 , and 528762 . Other All antagonists include those disclosed in International Patent Application, Publication Nos. WO 91/00277 , WO 91/00281 , WO 91/11909 , WO 91/11999 , WO 91/12001 , WO 91/12002 , WO 91/13063 , 91/15209 , WO 91/15479 , WO 91/16313 , WO 91/17148 , WO 91/18888 , WO 91/19697 , WO 91/19715 , WO 92/00067 , WO 92/00068 , WO 92/00977 , WO 92/02510 , WO 92/04335 , WO 92/04343 , WO 92/05161 , WO 92/06081 , WO 92/07834 , WO 92/07852 , WO 92/09278 , WO 92/09600 , WO 92/10189 , WO 92/11255 , WO 92/14714 , WO 92/16523 , WO 92/16552 , WO 92/17469 , WO 92/18092 , WO 92/19211 , WO 92/20651 , WO 92/20660 , WO 92/20687 , WO 92/21666 , WO 92/22533 , WO 93/00341 , WO 93/01177 , WO 93/03018 , WO 93/03033 and WO 93/03040 . The contents of the aforesaid European and International Patent Applications are hereby incorporated by reference thereto.
  • Preferred AT II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention include, but is not limited to, compounds with the following generic names: candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan.
  • Particularly preferred AT II antagonists or pharmaceutically acceptable derivatives thereof for use in the present invention are candesartan and candesartan cilexetil. Candesartan and candesartan cilexetil are known from European Patent No. 459 136 B1 , US 5,196,444 and US 5,703,110 to Takeda Chemical Industries. Candesartan cilexetil is currently manufactured and sold world-wide by AstraZeneca and Takeda.e.g. under the trade names Atacand®, Amias® and Blopress®.
  • NEP/ACE-inhibitors or pharmaceutically acceptable derivatives thereof, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF include, but is not limited to, those compounds disclosed in U.S. Patents Nos. 5,508,272 , 5,362,727 , 5,366,973 , 5,225,401 , 4,722,810 , 5,223,516 , 5,552,397 , 4,749,688 , 5,504,080 , 5,612,359 , 5,525,723 , 5,430,145 , and 5,679,671 , and European Patent Applications 0481522 , 0534263 , 0534396 , 0534492 and 0671172 .
  • Preferred NEP/ACE inhibitors for use in the present invention are those which are designated as preferred in the above U.S. patents and European Patent Applications and are incorporarted herein by reference. Especially preferrred is the NEP/ACE inhibitor omapatrilat (disclosed in U.S. Patent No. 5,508,272 ), or MDL100240 (disclosed in U.S. Patent No. 5,430,145 ).
  • Renin-inhibitors or pharmaceutically acceptable derivatives thereof, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF include, but is not limited to, the following compounds:
    • enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; CGP 29287; CGP 38560; SR 43845; U-71038; A 62198; and A 64662.
    Pharmaceutical formulations
  • In one aspect, the present invention relates to pharmaceutical formulations comprising as active ingredient an RAS inhibitor or a pharmaceutically acceptable derivative or prodrug thereof, including metabolites, for use in the prevention of stroke, diabetes and/or conge-stive heart failure (CHF).
  • For clinical use, the RAS inhibitor is formulated into a pharmaceutical formulation for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or some other mode of administration. The pharmaceutical formulation may contain the inhibitor in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • In the preparation of the pharmaceutical formulations of the present invention the active ingredient may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or pressed into tablets.
  • The active ingredient may be separately premixed with the other, non-active ingredients, before being mixed to form a formulation.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active ingredient of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain granules of the active ingredients. Hard gelatine capsules may also contain the active ingredients in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder to be recon-stituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation to by reconstituted with a suitable solvent before use.
  • The total amount of active ingredient suitably lies in the range of from about 0.1 % (w/w) to about 95 % (w/w) of the formulation, suitably from 0.5 % to 50 % (w/w) and preferably from 1 % to 25 % (w/w).
  • The pharmaceutical formulations may contain between about 0.1 mg and about 1000 mg of active ingredient, preferably between 1 mg and 100 mg of active ingredient.
  • The dose of the active ingredient to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician. The dosage will suitably be in the range of from about 0.01 mg/kg to about 20 mg/kg, preferably between 0.1 mg/kg and 10 mg/kg.
  • The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician. In general, dosages, and especially oral and parenteral dosages, will be in the range of from about 0.1 to about 100 mg per day of active ingredient, preferably between 1 and 50 mg per day of active ingredient.
  • The following Example is intended to illustrate, but in no way limit the scope of the invention.
    • EXAMPLE
  • A large-scale clinical trial was designed to examine the effect of the ACE inhibitor ramipril versus placebo in reducing cardiovascular events.
  • The study was conducted in 267 centres in 19 countries over a six year period and included 9,541 participants who are at high risk for cardiovascular events due to a history of previous ischaemic heart disease, stroke, peripheral arterial disease or individuals with diabetes.
  • The systolic blood pressure at inclusion of the patients was on average 138 mm Hg and thus the patients were normotensive at study start. After one month of therapy with either ramipril or placebo, the systolic blood pressure had decreased by 5.48 mm Hg and 1.59 mm Hg, respectively.
  • The primary endpoint of the study was myocardial infarction (MI), stroke and cardiovascular (CV) death (mortality).
  • The study was stopped early because of a very clear reduction in the combined endpoint of cardiovascular deaths, heart attacks and strokes in patients taking ramipril. In addition to the above benefits, there was also a reduction of between a fourth and a fifth in the need for revascularisation procedures (such as coronary artery bypass graft surgery, balloon angioplasty, etc.) and diabetic complications.
  • There was a clear 32% reduction in the ramipril group in the number of patients who developed a stroke, and this is surprising since patients were normotensive when recruited to the study.
  • The number of patients who developed CHF was significantly reduced by 21% in the ramipril group, which is unexpected since patients had no signs or symptoms of CHF at study start.
  • Equally surprising is the marked 36% reduction in the number of patients who developed diabetes in the ramipril group.
    • Abbrevations
    • ACE = angiotensin converting enzyme
    • AT II = angiotensin II type 1 receptor
    • CHF = congestive heart failure
    • IDMM = insulin-dependent, diabetes mellitus
    • JNC = Joint National Committee
    • MI = myocardial infarction
    • NIDDM = non-insulin-dependent diabetes mellitus
    • WHO = World Health Organization

Claims (20)

  1. The use of an angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention of stroke.
  2. The use of an angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention of stroke in patients exhibiting normal or low blood pressure.
  3. The use of an angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention of diabetes.
  4. The use of an inhibitor angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention of development of congestive heart failure (CHF) in patients with no preexisting CHF.
  5. The use according to any one of claims 1 to 4, wherein the AT II antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan.
  6. The use according to claim 5, wherein the AT II antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of candesartan and candesartan cilexetil.
  7. A method of prevention of stroke, comprising administering a therapeutically effective amount of an angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof, to a patient in need of such prevention.
  8. The method of prevention of stroke in patients exhibiting normal or low blood pressure, comprising administering a therapeutically effective amount of an angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof, to a patient in need of such prevention.
  9. The method of prevention of diabetes, comprising administering a therapeutically effective amount of an angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof, to a patient in need of such prevention.
  10. The method of prevention of development of CHF in patients with no preexisting CHF, comprising administering a therapeutically effective amount of angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof, to a patient in need of such prevention.
  11. The method of prevention according to any one of claims 7-10, wherein the AT II antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan.
  12. The method of prevention according to claim 11, wherein the AT II antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of candesartan and candesartan cilexetil.
  13. A pharmaceutical formulation for use in the prevention of stroke, diabetes and/or CHF, comprising a therapeutically effective amount of angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof.
  14. The pharmaceutical formulation according to claim 13, wherein the AT II antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan.
  15. The pharmaceutical formulation according to claim 14, wherein the AT II antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of candesartan and candesartan cilexetil.
  16. The pharmaceutical formulation according to any one of claims 13 to 15, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  17. The pharmaceutical formulation according to any one of claims 13 to 15, in unit dosage form.
  18. The use of an angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof, in the prevention of stroke, diabetes and/or CHF, by administering the angiotensin II type 1 receptor (AT II) antagonist or a pharmaceutically acceptable salt thereof, to a patient in need of such prevention.
  19. The use according to claim 18, wherein the AT II antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan.
  20. The use according to claim 19, wherein the AT II antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of candesartan and candesartan cilexetil.
EP08004265.8A 1999-08-27 2000-08-25 Use of Angiotensin II type 1 receptor antagonists for the prevention of diabetes Expired - Lifetime EP1925303B1 (en)

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SE9903028A SE9903028D0 (en) 1999-08-27 1999-08-27 New use
EP04006330A EP1437131B1 (en) 1999-08-27 2000-08-25 Use of ramipril for the prevention of diabetes in a patient with no preexisting congestive heart failure
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EP04006330A Division EP1437131B1 (en) 1999-08-27 2000-08-25 Use of ramipril for the prevention of diabetes in a patient with no preexisting congestive heart failure
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EP00965898.0A Expired - Lifetime EP1212081B2 (en) 1999-08-27 2000-08-25 Use of ramipril in the prevention of congestive heart failure
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Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SK2692002A3 (en) * 1999-08-30 2002-07-02 Aventis Pharma Gmbh Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events
RU2003131329A (en) 2001-03-26 2005-01-27 Котобуки Фармасьютикал Ко., Лтд. (Jp) Isoquinulidine Derivatives, Method for Their Preparation and Therapeutic Preparations Containing These Compounds
MXPA04003022A (en) * 2001-10-17 2004-07-05 Aventis Pharma Gmbh Method of reducing type 2 diabetes in high risk patients.
US6844361B2 (en) 2002-02-04 2005-01-18 Aventis Pharma Deutschland Gmbh Pharmaceutical composition comprising a sodium hydrogen exchange inhibitor and an angiotensin converting enzyme inhibitor
DE10230272A1 (en) * 2002-07-05 2004-01-22 Solvay Pharmaceuticals Gmbh 1 receptor antagonist for the prevention of secondary stroke
EP1382334A1 (en) * 2002-07-11 2004-01-21 Université de Picardie Jules Verne Use of angiotensin II AT1-receptor blockers (ARB), alone or combined with thiazide or angiotensin II for the treatment of stroke
US7232828B2 (en) * 2002-08-10 2007-06-19 Bethesda Pharmaceuticals, Inc. PPAR Ligands that do not cause fluid retention, edema or congestive heart failure
DE10306179A1 (en) * 2003-02-13 2004-08-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Composition useful for preventing stroke comprises dipyridamole or its salt, acetyl salicylic acid and an angiotensin II antagonist
US20040229901A1 (en) * 2003-02-24 2004-11-18 Lauren Otsuki Method of treatment of disease using an adenosine A1 receptor antagonist
CA2458288A1 (en) * 2003-03-11 2004-09-11 Institut De Cardiologie De Montreal / Montreal Heart Institute Method and compound to reduce the incidence of diabetes in a subject with chronic heart failure
EP1620107A1 (en) 2003-04-25 2006-02-01 Novacardia, Inc. Method of improved diuresis in individuals with impaired renal function
PL1687006T3 (en) 2003-11-18 2008-01-31 Solvay Pharm Gmbh Pharmaceutical compositions for the treatment of renal dysfunction
JP2007529459A (en) * 2004-03-17 2007-10-25 ノバルティス アクチエンゲゼルシャフト Use of renin inhibitors in therapy
CA2586760A1 (en) * 2004-11-05 2006-05-18 Edward S. Wilson Stabilized ramipril compositions and methods of making
WO2007044910A1 (en) * 2005-10-13 2007-04-19 Duke University Compositions for the treatment and prevention of heart disease and methods of using same
KR20090042976A (en) * 2006-08-28 2009-05-04 사노피-아벤티스 도이칠란트 게엠베하 How to lower glucose levels
WO2009017802A1 (en) 2007-08-01 2009-02-05 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Nitro-fattyacid modulation of type ii diabetes
CN102083787A (en) 2008-05-01 2011-06-01 康普雷克萨公司 Vinyl substituted fatty acids
US20140024713A1 (en) 2008-06-19 2014-01-23 University Of Utah Research Foundation Use of nitrated lipids for treatment of side effects of toxic medical therapies
WO2009155439A2 (en) 2008-06-19 2009-12-23 University Of Utah Research Foundation Use of nitrated lipids for treatment of side effects of toxic medical therapies
EP2350031A2 (en) 2008-08-20 2011-08-03 Ensemble Therapeutics Corporation Macrocyclic compounds for inhibition of tumor necrosis factor alpha
EP2459189A4 (en) 2009-07-31 2013-01-16 Univ Pittsburgh Fatty acids as anti-inflammatory agents
EP2483233A4 (en) 2009-10-02 2013-08-14 Complexa Inc Heteroatom containing substituted fatty acids
EP2568893B1 (en) 2010-05-14 2015-06-24 Sabanci Universitesi An apparatus for using hydrodynamic cavitation in medical treatment
WO2013028501A1 (en) * 2011-08-19 2013-02-28 The University Of Utah Research Foundation Combination therapy with nitrated lipids and inhibitors of the renin-angiotensin-aldosterone system
WO2016176338A1 (en) * 2015-04-30 2016-11-03 The Trustees Of Columbia University In The City Of New York Small molecule ras ligands
IL280619B2 (en) 2015-07-07 2023-10-01 H Lundbeck As Pde9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases
IL258476B2 (en) 2015-10-02 2023-04-01 Complexa Inc Prevention, treatment and reversal of disease using therapeutically effective amounts of activated fatty acids
EP4349403A3 (en) 2018-05-25 2024-06-05 Cardurion Pharmaceuticals, Inc. Monohydrate and crystalline forms of 6-[(3s,4s)-4-methyl-1- (pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl- 7h-imid azo [1,5- a] pyrazin-8-one
CN110833620A (en) * 2018-08-15 2020-02-25 王镕 Use of angiotensin converting enzyme inhibitors for the prevention and treatment of autoimmune diseases and the corresponding complications
MA53501A (en) 2018-08-31 2021-07-07 Imara Inc PDE9 INHIBITORS FOR THE TREATMENT OF SICKLE CELL DISEASE
KR20230137654A (en) * 2022-03-22 2023-10-05 주식회사 메디포럼 A composition for preventing and treating stroke

Citations (184)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0079022A2 (en) 1981-11-05 1983-05-18 Hoechst Aktiengesellschaft Derivatives of cis, endo-2-azabicyclo-(3.3.0)-octane-3-carboxylic acid, process for their preparation, medicines containing them and their use
EP0158927A2 (en) 1984-04-12 1985-10-23 Hoechst Aktiengesellschaft Process for the treatment of heart failure
EP0253310A2 (en) 1986-07-11 1988-01-20 E.I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
US4722810A (en) 1984-08-16 1988-02-02 E. R. Squibb & Sons, Inc. Enkephalinase inhibitors
US4743450A (en) 1987-02-24 1988-05-10 Warner-Lambert Company Stabilized compositions
US4749688A (en) 1986-06-20 1988-06-07 Schering Corporation Use of neutral metalloendopeptidase inhibitors in the treatment of hypertension
EP0317878A1 (en) 1987-11-24 1989-05-31 Hoechst Aktiengesellschaft Stabilized pharmaceutical agents, process for preparing them, and stable pharmaceutical preparations
EP0323841A2 (en) 1988-01-07 1989-07-12 E.I. Du Pont De Nemours And Company Substituted pyrrole, pyrazole and triazole angiotensin II antagonists
EP0324377A2 (en) 1988-01-07 1989-07-19 E.I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles and combinations thereof with diuretics and NSaids
US4857520A (en) 1987-02-14 1989-08-15 Hoechst Aktiengesellschaft Fused azepinone and azocinone derivatives, processes for their preparation, agents containing them and their use, and intermediates in their preparation
EP0399731A1 (en) 1989-05-23 1990-11-28 Zeneca Limited Azaindenes
EP0400974A2 (en) 1989-05-30 1990-12-05 Merck & Co. Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
EP0401030A2 (en) 1989-06-01 1990-12-05 Merck & Co. Inc. Angiotensin II antagonists
EP0403158A2 (en) 1989-06-14 1990-12-19 Smithkline Beecham Corporation Imidazolyl-alkenoic acids
EP0403159A2 (en) 1989-06-14 1990-12-19 Smithkline Beecham Corporation Imidazolyl-alkenoic acids
EP0407342A2 (en) 1989-07-06 1991-01-09 Ciba-Geigy Ag Pyrimidine derivatives
EP0407102A1 (en) 1989-07-03 1991-01-09 Merck & Co. Inc. Substituted imidazo-fused 5-membered ring heterocycles as angiotensin II antagonists
WO1991000281A2 (en) 1989-06-30 1991-01-10 E.I. Du Pont De Nemours And Company Fused-ring aryl substituted imidazoles
WO1991000277A1 (en) 1989-06-30 1991-01-10 E.I. Du Pont De Nemours And Company Substituted imidazoles
EP0409332A2 (en) 1989-07-19 1991-01-23 Merck & Co. Inc. Substituted triazoles as angiotensin II antagonists
EP0411507A1 (en) 1989-08-02 1991-02-06 Takeda Chemical Industries, Ltd. Pyrazole derivatives, their production and use
EP0411766A1 (en) 1989-07-03 1991-02-06 Merck & Co. Inc. Substituted quinazolinones as angiotensin II antagonists
EP0412594A2 (en) 1989-07-28 1991-02-13 Merck & Co. Inc. Substituted triazolinones, triazolinethiones, and triazolinimines as angiotensin II antagonists
EP0412848A2 (en) 1989-08-11 1991-02-13 Zeneca Limited Quinoline derivatives, process for their preparation and their use as medicaments
EP0415886A2 (en) 1989-08-30 1991-03-06 Ciba-Geigy Ag Aza compounds
EP0419048A2 (en) 1989-08-28 1991-03-27 Merck & Co. Inc. Substituted pyrimidinones as angiotensin II antagonists
EP0420237A1 (en) 1989-09-29 1991-04-03 Eisai Co., Ltd. Biphenylmethane derivative, the use of it and pharmacological compositions containing same
EP0424317A2 (en) 1989-10-19 1991-04-24 Ciba-Geigy Ag Pyrimidines
EP0425211A1 (en) 1989-10-25 1991-05-02 Smithkline Beecham Corporation Substituted 5-((tetrazolyl)alkenyl)-imidazoles
EP0425921A1 (en) 1989-10-24 1991-05-08 Takeda Chemical Industries, Ltd. Benzimidazole derivatives, their production and use
EP0426021A1 (en) 1989-10-31 1991-05-08 Fujisawa Pharmaceutical Co., Ltd. Condensed imidazole derivatives and processes for preparation thereof
EP0427463A1 (en) 1989-11-06 1991-05-15 Smithkline Beecham Corporation Substituted N-(imidazolyl)alkyl alanine derivatives
EP0429257A2 (en) 1989-11-17 1991-05-29 Glaxo Group Limited Indole derivatives
EP0430709A2 (en) 1989-12-01 1991-06-05 Glaxo Group Limited Benzthiophen derivatives
EP0430300A2 (en) 1989-12-01 1991-06-05 Takeda Chemical Industries, Ltd. Xanthine derivatives, their production and use
EP0432737A1 (en) 1989-12-11 1991-06-19 G.D. Searle & Co. Cycloheptimidazolone compounds as angiotensin II antagonists for control of hypertension
EP0434249A2 (en) 1989-12-01 1991-06-26 Glaxo Group Limited Benzofuran derivatives
EP0434038A1 (en) 1989-12-22 1991-06-26 Takeda Chemical Industries, Ltd. Fused imidazole derivatives, their production and use
EP0435827A2 (en) 1989-12-28 1991-07-03 Ciba-Geigy Ag Diaza compounds
EP0437103A2 (en) 1989-12-29 1991-07-17 Smithkline Beecham Corporation Substituted 5-(alkyl)carboxamide imidazoles
EP0438869A1 (en) 1989-11-30 1991-07-31 Eli Lilly And Company Improvements in and relating to angiotensin II antagonists
EP0442473A1 (en) 1990-02-15 1991-08-21 Takeda Chemical Industries, Ltd. Pyrimidinedione derivatives, their production and use
WO1991011999A1 (en) 1990-02-13 1991-08-22 Merck & Co., Inc. Angiotensin ii antagonists incorporating a substituted benzyl element
WO1991012002A1 (en) 1990-02-13 1991-08-22 Merck & Co., Inc. Imidazole angiotensin ii antagonists incorporating a substituted benzyl element
WO1991011909A1 (en) 1990-02-13 1991-08-22 Merck & Co., Inc. Triazole angiotensin ii antagonists incorporating a substituted benzyl element
EP0443568A1 (en) 1990-02-22 1991-08-28 Takeda Chemical Industries, Ltd. Fused thiophene derivatives, their production and use
EP0443983A1 (en) 1990-02-19 1991-08-28 Ciba-Geigy Ag Acyl compounds
WO1991013063A1 (en) 1990-03-01 1991-09-05 Schering Aktiengesellschaft Berlin Und Bergkamen New benzimidazole derivatives, method for preparing them and their pharmaceutical use
EP0446062A1 (en) 1990-03-09 1991-09-11 Glaxo Group Limited C-Linked pyrazole derivatives
EP0445811A2 (en) 1990-03-07 1991-09-11 Takeda Chemical Industries, Ltd. Nitrogen-containing heterocyclic compounds, their production and use
EP0449699A2 (en) 1990-03-19 1991-10-02 Laboratoires Upsa Pyrazole derivatives as angiotensin II-receptor antagonists, process for their preparation and pharmaceutical compositions containing them
EP0450566A1 (en) 1990-04-04 1991-10-09 Hoechst Aktiengesellschaft Substituted azoles, method for their preparation, these containing compositions and their use
WO1991015479A1 (en) 1990-03-30 1991-10-17 Merck & Co., Inc. Substituted pyrazoles, isoxazoles and isothiazoles
WO1991015209A1 (en) 1990-03-30 1991-10-17 Merck & Co., Inc. Substituted pyrimidines, pyrimidinones and pyridopyrimidines
EP0453210A2 (en) 1990-04-19 1991-10-23 Zeneca Limited Pyridine derivatives
EP0454511A1 (en) 1990-03-20 1991-10-30 Sanofi N-substituted heterocycle derivatives, their preparation, compositions containing them
WO1991016313A1 (en) 1990-04-13 1991-10-31 Smithkline Beecham Corporation Substituted benzimidazoles
EP0454831A1 (en) 1989-11-20 1991-11-06 Ici Plc Diazine derivatives as angiotensin II receptor antagonists.
EP0456442A1 (en) 1990-05-09 1991-11-13 Zeneca Limited Quinoline derivatives, process for their preparation and their use as medicaments
EP0456510A1 (en) 1990-05-11 1991-11-13 Merck & Co. Inc. Antihypertensive products, a process for their preparation and pharamaceutical compositions containing them
WO1991017148A1 (en) 1990-05-04 1991-11-14 G.D. Searle & Co. 1h-substituted-1,2,4-triazole compounds for treatment of cardiovascular disorders
EP0459136A1 (en) 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Benzimidazole derivatives, their production and use
EP0461040A1 (en) 1990-06-08 1991-12-11 Roussel Uclaf Imidazol derivatives, their process for production, intermediates, their application as medicaments and the pharmaceutical compositions containing them
EP0461039A1 (en) 1990-06-08 1991-12-11 Roussel Uclaf Benzimidazole derivatives, process and intermediates for their preparation, their use as medicaments and pharmaceutical compositions containing them
WO1991018888A1 (en) 1990-05-25 1991-12-12 G.D. Searle & Co. N-substituted-1,2,4-triazolone compounds for treatment of cardiovascular disorders
WO1991019715A1 (en) 1990-06-15 1991-12-26 G.D. Searle & Co. 1H-SUBSTITUTED-IMIDAZO[4,5-d]PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS
WO1991019697A1 (en) 1990-06-19 1991-12-26 Meiji Seika Kabushiki Kaisha Pyridine derivative with angiotensin ii antagonism
EP0465323A1 (en) 1990-07-02 1992-01-08 Laboratoires Upsa Pyrimidin derivatives, angiotensin II receptor antagonists, their process of preparation and pharmaceutical compositions containing them
EP0465368A1 (en) 1990-07-05 1992-01-08 Roussel Uclaf Sulfur derivatives of imidazole, process for their preparation, intermediates, their use as medicaments, and pharmaceutical compositions containing them
WO1992000068A1 (en) 1990-06-28 1992-01-09 Smithkline Beecham Corporation Substituted histidines
WO1992000067A2 (en) 1990-06-22 1992-01-09 E.I. Du Pont De Nemours And Company Treatment of chronic renal failure with imidazole angiotensin-ii receptor antagonists
EP0467207A2 (en) 1990-07-18 1992-01-22 F. Hoffmann-La Roche Ag Purinderivate
EP0467715A1 (en) 1990-07-19 1992-01-22 Merck & Co. Inc. Microbial transformation process for antihypertensive products
WO1992000977A2 (en) 1990-07-13 1992-01-23 E.I. Du Pont De Nemours And Company 4-alkylimidazole derivatives
EP0468470A1 (en) 1990-07-23 1992-01-29 Dr. Karl Thomae GmbH Benzimidazoles, medicaments containing them and process for their preparation
EP0468372A2 (en) 1990-07-21 1992-01-29 Hoechst Aktiengesellschaft Substituted azoles, process for their preparation and their use
EP0470543A1 (en) 1990-08-10 1992-02-12 Dr. Karl Thomae GmbH Heterocyclic imidazoles, remedies containing them and processes for their preparation
WO1992002510A1 (en) 1990-07-31 1992-02-20 Smithkline Beecham Corporation Substituted [1h-imidazol-5-yl]alkanoic acids
EP0475206A2 (en) 1990-09-10 1992-03-18 Abbott Laboratories Angiotensin II receptor antagonists
EP0475898A1 (en) 1990-09-10 1992-03-18 Ciba-Geigy Ag Azacyclic compounds
WO1992004335A2 (en) 1990-08-28 1992-03-19 G.D. Searle & Co. Renal-selective biphenylalkyl 1h-substituted-1,2,4-triazole angiotensin ii antagonists for treatment of hypertension
WO1992004343A1 (en) 1990-09-04 1992-03-19 Yamanouchi Pharmaceutical Co., Ltd. Novel tetrahydrobenzazole derivative
WO1992005161A1 (en) 1990-09-19 1992-04-02 G.D. Searle & Co. 1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders
EP0479479A1 (en) 1990-10-01 1992-04-08 Merck & Co. Inc. Imadazole angiotensin II antagonists incorporating acidic functional groups
EP0480659A2 (en) 1990-10-08 1992-04-15 Merck & Co. Inc. Use of Angiotensin-II antagonists for the manufacture of a medicament for the treatment of hyperuricemia
EP0480204A1 (en) 1990-09-25 1992-04-15 Fujisawa Pharmaceutical Co., Ltd. Imidazole derivatives, potent and selective antagonists of angiotensin II receptor
WO1992006081A1 (en) 1990-09-28 1992-04-16 Warner-Lambert Company Anilide derivatives with angiotensin ii antagonist properties
EP0481614A1 (en) 1990-10-01 1992-04-22 Merck & Co. Inc. Substituted pyridopyrimidinones and related heterocycles as angiotensin II antagonists
EP0481522A1 (en) 1990-10-18 1992-04-22 Merrell Pharmaceuticals Inc. Novel mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
EP0481448A1 (en) 1990-10-16 1992-04-22 E.R. SQUIBB & SONS, INC. Dihydropyrimidine derivatives
EP0483683A2 (en) 1990-10-30 1992-05-06 Takeda Chemical Industries, Ltd. Thienoimidazole derivatives, their production and use
WO1992007834A1 (en) 1990-10-31 1992-05-14 G.D. Searle & Co. N-substituted imidazol-2-one compounds for treatment of circulatory disorders
WO1992007852A1 (en) 1990-10-25 1992-05-14 G.D. Searle & Co. Biphenylalkyl xanthine compounds for treatment of cardiovascular disorders
EP0485929A1 (en) 1990-11-16 1992-05-20 Hoechst Aktiengesellschaft Substituted azoles, process for their preparation and their application
EP0487252A1 (en) 1990-11-19 1992-05-27 Zeneca Limited Quinoline and 1,5-Naphthyridine derivatives, process and intermediates for their preparation and pharmaceutical compositions containing them
EP0488532A1 (en) 1990-10-31 1992-06-03 E.R. Squibb & Sons, Inc. Indole- and benzimidazole-substituted imidazole and benzimidazole derivatives
WO1992009278A1 (en) 1990-11-30 1992-06-11 Smithkline Beecham Corporation Substituted 5-aryl imidazoles
WO1992009600A1 (en) 1990-11-29 1992-06-11 Glaxo Group Limited Benzofuran and benzthiophene derivatives
EP0490820A2 (en) 1990-12-14 1992-06-17 Ciba-Geigy Ag Biphenylyl compounds
EP0490587A1 (en) 1990-12-07 1992-06-17 Merck & Co. Inc. Substituted pyrazolopyrimidines and imidazopyridazines as angiotensin II antagonists
WO1992010189A1 (en) 1990-12-14 1992-06-25 Smithkline Beecham Corporation Imidazolyl-alkenoic acids
EP0492105A2 (en) 1990-11-17 1992-07-01 Hoechst Aktiengesellschaft Treatment of cardiac hypertrophy with angiotensin-II-receptor-blockers
WO1992011255A1 (en) 1990-12-20 1992-07-09 G.D. Searle & Co. N-SUBSTITUTED N-(α-TRIAZOLYL-TOLUYL)PYRROLE COMPOUNDS FOR TREATMENT OF CIRCULATORY DISORDERS
EP0497150A1 (en) 1991-01-30 1992-08-05 American Cyanamid Company Angiotensin II receptor blocking 2,3,6-substituted quinazolones
EP0497121A1 (en) 1991-01-31 1992-08-05 Chemisch Pharmazeutische Forschungsgesellschaft m.b.H. Tetrazole derivatives, process for their production and their application
EP0497516A1 (en) 1991-01-30 1992-08-05 Merck & Co. Inc. Substituted pyrrolo-fused 6-membered heterocycles as angiotensin II antagonists
EP0498721A1 (en) 1991-02-07 1992-08-12 Roussel Uclaf N-substituted quinoline derivatives, process for their preparation, intermediates obtained, their use as pharmaceuticals and pharmaceutical compositions containing them
EP0498722A1 (en) 1991-02-07 1992-08-12 Roussel Uclaf Bicyclic nitrogen compounds, their preparation, intermediates obtained, their use as pharmaceuticals and pharmaceutical compositions containing them
EP0498723A1 (en) 1991-02-07 1992-08-12 Roussel Uclaf Nitrogen containing bicycle compounds, method for their preparation, their use as pharmaceutical and compositions containing them
EP0499414A2 (en) 1991-02-11 1992-08-19 Zeneca Limited Pyridine derivatives as angiotensin II antagonists, processes for their preparation and pharmaceutical compositions containing them
EP0499416A2 (en) 1991-02-11 1992-08-19 Zeneca Limited Pyridine compounds as angiotensin II antagonists, processes for their preparation and pharmaceutical compositions containing them
EP0499415A1 (en) 1991-02-11 1992-08-19 Zeneca Limited Pyridine and quinoline derivatives, processes for their manufacture and their use as angiotensin II antagonists
EP0500409A1 (en) 1991-02-20 1992-08-26 Synthelabo 4-Pyrimidinone derivatives, their preparation and their application in therapy
EP0500297A1 (en) 1991-02-16 1992-08-26 FISONS plc Substituted pyridinones and pyrimidinones as angiotensin II antagonists
EP0501892A1 (en) 1991-03-01 1992-09-02 Sanofi Diazotized heterocyclic derivatives N-substituted by a biphenylmethyl group, their preparation and pharmaceutical compositions containing them
EP0501269A1 (en) 1991-02-26 1992-09-02 E.R. SQUIBB & SONS, INC. Imidazole and benzimidazole derivatives
EP0502575A1 (en) 1991-03-06 1992-09-09 Merck & Co. Inc. Substituted 1-(2H)-isoquinolinones
EP0502725A2 (en) 1991-03-06 1992-09-09 Merck & Co. Inc. Substituted fused pyrimidinones
EP0502314A1 (en) 1991-02-06 1992-09-09 Dr. Karl Thomae GmbH Benzimidazol, medicaments containing them and process for their preparation
EP0503162A1 (en) 1991-01-04 1992-09-16 Hoechst Aktiengesellschaft Azole derivatives, process for their preparation and their application
EP0503838A2 (en) 1991-03-08 1992-09-16 Merck & Co. Inc. Heterocyclic compounds bearing acidic functional groups as angiotensin II antagonists
EP0503785A1 (en) 1991-02-21 1992-09-16 Sankyo Company Limited 1-Biphenylimidazole derivatives, their preparation and their therapeutic use
EP0505111A2 (en) 1991-03-22 1992-09-23 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted imidazo (1,2-b)(1,2,4) triazole
EP0504888A1 (en) 1991-03-21 1992-09-23 G.D. Searle & Co. 5-Arylheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders
EP0505098A1 (en) 1991-03-19 1992-09-23 Merck & Co. Inc. Imidazole derivatives bearing acidic functional groups as angiotensin II antagonists
EP0505954A1 (en) 1991-03-25 1992-09-30 Glaxo Group Limited N-Imidazolylmethyl benzofuran derivatives as inhibitors of angiotensin II activity
EP0505893A1 (en) 1991-03-27 1992-09-30 MERCK PATENT GmbH Imidazopyridines
EP0507594A1 (en) 1991-04-05 1992-10-07 Merck & Co. Inc. Substituted quinolines as angiotensin II antagonists
EP0508445A1 (en) 1991-04-12 1992-10-14 G.D. Searle & Co. 1-Arylheteroarylalkyl substituted-1H-1,2,4-triazole compounds for treatment of circulatory disorders
EP0508393A1 (en) 1991-04-05 1992-10-14 G.D. Searle & Co. N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders
EP0508723A1 (en) 1991-04-08 1992-10-14 Merck & Co. Inc. Angiotensin II antagonists incorporating an indole or dihydroindole
EP0510812A1 (en) 1991-04-26 1992-10-28 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted thiophene or furan
EP0510813A1 (en) 1991-03-25 1992-10-28 Merck & Co. Inc. Angiotensin II antagonists incorporating a nitrogen containing six membered ring heterocycle
EP0511791A2 (en) 1991-04-30 1992-11-04 Zeneca Limited Pyrrolopyridine derivatives as Angiotensin inhibitors
EP0511767A1 (en) 1991-04-29 1992-11-04 Merck & Co. Inc. Tablets containing compound DUP753
EP0512870A1 (en) 1991-05-10 1992-11-11 Merck & Co. Inc. Substituted quinazolinones bearing acidic functional groups as angiotensin II antagonists
EP0512675A1 (en) 1991-05-07 1992-11-11 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted thiophene or furan
EP0512676A1 (en) 1991-05-07 1992-11-11 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted benzyl element
WO1992019211A2 (en) 1991-05-08 1992-11-12 The Upjohn Company Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same
EP0514193A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited N-linked imidazolyl-methyl benzofuran derivatives with antihypotensive activity
EP0514216A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited Antihypotensive benzofuran derivatives with N-linked 1H-imidazolyl-methyl-5-carboxamide substituents
EP0514198A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited 1H-Imidazol-1-yl-methyl benzofuran derivatives with the imidazolyl moiety being substituted by a cycloalkyl group
EP0513979A1 (en) 1991-03-26 1992-11-19 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted thiophene or furan
EP0514192A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited Antihypertensive benzofuran derivatives, substituted by varied N-pyrimidinyl- or N-imidazolyl-methyl groups
EP0514217A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited Antihypertensive benzofuran derivatives carrying 4-pyrazolylmethyl substituents
EP0514197A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited Anti-hypertensive benzofuran derivatives substituted by N-imidazolyl-methyl groups which are condensed with optionally nitrogen containing, six-membered rings
EP0513533A2 (en) 1991-04-26 1992-11-19 Bayer Ag Heterocyclic substituted phenylacetic-acid derivatives, process for their preparation and their pharmaceutical application
EP0515265A1 (en) 1991-05-23 1992-11-25 Roussel Uclaf Pyrimidin derivates, process for their preparation, the obtained intermediates, their use as medicines and the pharmaceutical compositions containing them
WO1992020651A2 (en) 1991-05-15 1992-11-26 Smithkline Beecham Corporation N-(heteroaryl)-imidazolyl-alkenoic acids
WO1992020660A1 (en) 1991-05-10 1992-11-26 Merck & Co., Inc. Substituted 1-(2h)-isoquinolinones bearing acidic functional groups as angiotensin ii antagonists
WO1992020687A1 (en) 1991-05-10 1992-11-26 Merck & Co., Inc. Substituted pyrimidinones bearing acidic functional groups as angiotensin ii antagonists
EP0516392A2 (en) 1991-05-31 1992-12-02 Zeneca Limited Naphthyridine derivatives as angiotensin II inhibitors
EP0515357A1 (en) 1990-02-14 1992-12-02 Siemens Ag METHOD FOR DEMODULATING SECAM-CODED COLOR TELEVISION SIGNALS WITH LINKED CLOCK AND CIRCUIT ARRANGEMENT FOR IMPLEMENTING THE METHOD.
EP0517357A1 (en) 1991-06-05 1992-12-09 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted indole or dihydroindole
WO1992021666A1 (en) 1991-05-31 1992-12-10 Laboratoires Upsa Angiotensin ii receptor antagonist thiazole devivatives
EP0518033A1 (en) 1991-04-16 1992-12-16 Takeda Chemical Industries, Ltd. Fused heterocyclic compounds, their production and use
WO1992022533A1 (en) 1991-06-14 1992-12-23 The Upjohn Company 4-aminoquinolines and pharmaceutical compositions thereof
EP0518931A1 (en) 1990-03-05 1992-12-23 Membrane Technology And Research, Inc. Refrigeration process with purge and recovery of refrigerant
EP0520724A1 (en) 1991-06-25 1992-12-30 Zeneca Limited Angiotensin II antagonists
EP0520723A1 (en) 1991-06-25 1992-12-30 Imperial Chemical Industries Plc Angiotensin II antagonists
EP0520423A2 (en) 1991-06-27 1992-12-30 Takeda Chemical Industries, Ltd. Heterocyclic compounds, their production and use as angiotensin II antagonists
EP0521768A1 (en) 1991-07-05 1993-01-07 Laboratoires Upsa Thiazolopyrimidine derivatives as angiotensin II-receptor antagonists: processes for their preparation and pharmaceutical compositions containing them
WO1993000341A1 (en) 1991-06-21 1993-01-07 Warner-Lambert Company 4-(1-h-pyrrol-1-yl)imidazoles with angiotensin ii antagonist activity
WO1993001177A1 (en) 1991-07-03 1993-01-21 Merck & Co., Inc. Substituted triazolinones
EP0527534A1 (en) 1991-08-13 1993-02-17 Merck & Co. Inc. Quinoline and azaquinoline angiotensin II antagonists
WO1993003018A1 (en) 1991-08-02 1993-02-18 Istituto Luso Farmaco D'italia S.P.A. Compounds having angiotensine ii antagonistic activity
WO1993003040A1 (en) 1991-08-05 1993-02-18 Taisho Pharmaceutical Co., Ltd. Thienopyrimidin-4-one derivative
WO1993003033A1 (en) 1991-07-26 1993-02-18 G. D. Searle & Co. CARBONATE-SUBSTITUTED IMIDAZO[4,5-d] PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS
EP0528762A1 (en) 1991-08-15 1993-02-24 Ciba-Geigy Ag N-acyl-N-heterocyclyl- or naphthyl-alkyl amino acids as angiotensin II antagonists
EP0534263A1 (en) 1991-09-20 1993-03-31 L.G.L. ELECTRONICS S.p.A. Self-adjusting thread braking device for weft feeder units
EP0534492A2 (en) 1991-09-27 1993-03-31 Merrell Pharmaceuticals Inc. Carboxyalkyl substituted inhibitors of enkephalinase and ACE
EP0534396A2 (en) 1991-09-27 1993-03-31 Merrell Pharmaceuticals Inc. 2-Substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ace
US5223516A (en) 1990-03-22 1993-06-29 E. R. Squibb & Sons, Inc. 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same
US5225401A (en) 1991-08-12 1993-07-06 E. R. Squibb & Sons, Inc. Treatment of congestive heart failure
US5362727A (en) 1993-07-26 1994-11-08 Bristol-Myers Squibb Substituted azepino[2,1-a]isoquinoline compounds
US5366973A (en) 1992-05-15 1994-11-22 Merrell Dow Pharmaceuticals Inc. Mercaptoacetylamido pyridazo [1,2]pyridazine, pyrazolo[1,2]pyridazine pyrazolo[1,2]pyridazine, pyridazol[1,2-a][1,2]diazepine and pyrazolol[1,2-a][1,2]diazepine
US5430145A (en) 1990-10-18 1995-07-04 Merrell Dow Pharmaceuticals Inc. Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
EP0671172A1 (en) 1993-06-11 1995-09-13 Eisai Co., Ltd. Amino acid derivative
US5504080A (en) 1992-10-28 1996-04-02 Bristol-Myers Squibb Co. Benzo-fused lactams
US5508272A (en) 1993-06-15 1996-04-16 Bristol-Myers Squibb Company Compounds containing a fused bicycle ring and processes therefor
US5525723A (en) 1993-11-18 1996-06-11 Bristol-Myers Squibb Co. Compounds containing a fused multiple ring lactam
US5552397A (en) 1992-05-18 1996-09-03 E. R. Squibb & Sons, Inc. Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase
US5612359A (en) 1994-08-26 1997-03-18 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides
US5703110A (en) 1990-04-27 1997-12-30 Takeda Chemical Industries, Ltd. Benzimidazole derivatives, their production and use

Family Cites Families (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5612114B2 (en) * 1974-06-07 1981-03-18
US4231938A (en) * 1979-06-15 1980-11-04 Merck & Co., Inc. Hypocholesteremic fermentation products and process of preparation
US4444784A (en) * 1980-08-05 1984-04-24 Merck & Co., Inc. Antihypercholesterolemic compounds
DK149080C (en) * 1980-06-06 1986-07-28 Sankyo Co METHOD FOR PREPARING ML-236B CARBOXYLIC ACID DERIVATIVES
US4450171A (en) * 1980-08-05 1984-05-22 Merck & Co., Inc. Antihypercholesterolemic compounds
ZA817261B (en) * 1980-10-23 1982-09-29 Schering Corp Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them
US4448784A (en) * 1982-04-12 1984-05-15 Hoechst-Roussel Pharmaceuticals, Inc. 1-(Aminoalkylphenyl and aminoalkylbenzyl)-indoles and indolines and analgesic method of use thereof
US4739073A (en) * 1983-11-04 1988-04-19 Sandoz Pharmaceuticals Corp. Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof
US5684016A (en) * 1984-04-12 1997-11-04 Hoechst Aktiengesellschaft Method of treating cardiac insufficiency
US5231080A (en) * 1985-10-15 1993-07-27 Hoechst Aktiengesellschaft Method for the treatment of atherosclerosis, thrombosis, and peripheral vessel disease
EP0241201A3 (en) * 1986-04-07 1990-05-23 Merck & Co. Inc. Angiotensin converting enzyme inhibitors useful in prolonging survival of mammalians with congestive heart failure
US4681893A (en) * 1986-05-30 1987-07-21 Warner-Lambert Company Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
DE3633496A1 (en) * 1986-10-02 1988-04-14 Hoechst Ag COMBINATION OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS WITH CALCIUMANTAGONISTS AND THEIR USE IN MEDICINAL PRODUCTS
FR2607004B1 (en) * 1986-11-20 1990-06-01 Synthelabo PHARMACEUTICAL COMPOSITIONS CONTAINING DILTIAZEM AND AN ANGIOTENSIN CONVERSION ENZYME INHIBITOR
EP0331014A3 (en) * 1988-03-02 1991-10-23 THERA - Patent Verwaltungs-GmbH Use of ace inhibitors in diabetes prophylaxis
US5217958A (en) * 1988-03-03 1993-06-08 E. R. Squibb & Sons, Inc. 1,2-hydroxy phosphonates and derivatives thereof
US4804770A (en) * 1988-04-29 1989-02-14 E. R. Squibb & Sons, Inc. Process for preparing a keto-phosphonate intermediate useful in preparing HMG-CoA reductase inhibitors
DE3818245A1 (en) * 1988-05-28 1989-12-07 Hoechst Ag COMBINATION OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS WITH COLD CHANNEL MODULATORS AND THEIR USE IN MEDICINAL PRODUCTS
WO1990005531A1 (en) * 1988-11-21 1990-05-31 Abbott Laboratories Method for treating vascular diseases
CA2016467A1 (en) * 1989-06-05 1990-12-05 Martin Eisman Method for treating peripheral atherosclerotic disease employing an hmg coa reductase inhibitor and/or a squalene synthetase inhibitor
FI94339C (en) * 1989-07-21 1995-08-25 Warner Lambert Co Process for the preparation of pharmaceutically acceptable [R- (R *, R *)] - 2- (4-fluorophenyl) -, - dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H- for the preparation of pyrrole-1-heptanoic acid and its pharmaceutically acceptable salts
DE3926606A1 (en) * 1989-08-11 1991-02-14 Hoechst Ag METHOD FOR THE TREATMENT OF CARDIALS AND VASCULAR HYPERTROPHY AND HYPERPLASIA
US5098924A (en) * 1989-09-15 1992-03-24 E. R. Squibb & Sons, Inc. Diol sulfonamide and sulfinyl renin inhibitors
US5061694A (en) * 1989-10-23 1991-10-29 E. R. Squibb & Sons, Inc. Method for stabilizing or causing regression of atherosclerosis in coronary arteries employing an ace inhibitor
US5212165A (en) * 1989-10-23 1993-05-18 E. R. Squibb & Sons, Inc. Method for rehabilitating the vasorelaxant action of the coronary arteries impaired through atherosclerosis or hypercholesterolemia employing an ace inhibitor
CA2026686A1 (en) * 1989-10-30 1991-05-01 Werner Tschollar Method for preventing onset of type ii diabetes employing an ace inhibitor
US5298497A (en) * 1990-05-15 1994-03-29 E. R. Squibb & Sons, Inc. Method for preventing onset of hypertension employing a cholesterol lowering drug
US5140012A (en) * 1990-05-31 1992-08-18 E. R. Squibb & Sons, Inc. Method for preventing onset of restenosis after angioplasty employing pravastatin
US5166143A (en) * 1990-05-31 1992-11-24 E. R. Squibb & Sons, Inc. Method for preventing onset of restenosis after angioplasty employing an ace inhibitor
US5622985A (en) * 1990-06-11 1997-04-22 Bristol-Myers Squibb Company Method for preventing a second heart attack employing an HMG CoA reductase inhibitor
CA2048699A1 (en) * 1990-09-04 1992-03-05 Abraham Sudilovsky Method for preventing or treating cerebro-vascular disease employing ceronapril
US5470975A (en) * 1990-10-16 1995-11-28 E.R. Squibb & Sons, Inc. Dihydropyrimidine derivatives
US5130333A (en) * 1990-10-19 1992-07-14 E. R. Squibb & Sons, Inc. Method for treating type II diabetes employing a cholesterol lowering drug
US5190970A (en) * 1990-10-19 1993-03-02 E. R. Squibb & Sons, Inc. Method for preventing onset of or treating Type II diabetes employing a cholesterol lowering drug alone or in combination with an ace inhibitor
CA2052014A1 (en) * 1990-10-19 1992-04-20 Henry Y. Pan Method for preventing diabetic complications employing a cholesterol lowering drug alone or in combination with an ace inhibitor
US5157025A (en) * 1991-04-01 1992-10-20 E. R. Squibb & Sons, Inc. Method for lowering serum cholesterol employing a phosphorus containing ace inhibitor alone or in combination with a cholesterol lowering drug
US5506361A (en) * 1991-05-08 1996-04-09 Theupjohn Company Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same
US5202322A (en) * 1991-09-25 1993-04-13 Merck & Co., Inc. Quinazolinone and pyridopyrimidine a-II antagonists
US5256667A (en) * 1991-09-25 1993-10-26 Merck & Co., Inc. Quinazolinones and pyridopyrimidinones
JPH06107661A (en) * 1991-10-24 1994-04-19 Upjohn Co:The Imidazole derivative and medicinal composition having same as effective component
US5219856A (en) * 1992-04-06 1993-06-15 E. I. Du Pont De Nemours And Company Angiotensin-II receptor blocking, heterocycle substituted imidazoles
US5972990A (en) * 1992-04-10 1999-10-26 Brigham And Women's Hospital, Inc. Methods for reducing risk of repeat myocardial infarction and increasing survival in heart attack victims
US5977160A (en) * 1992-04-10 1999-11-02 Brigham And Women's Hospital, Inc. Methods for reducing risk of repeat myocardial infarction and increasing survival in heart attack victims
CA2139779A1 (en) * 1992-07-17 1994-02-03 Ralph A. Rivero Substituted biphenylmethylimidazopyridines
US5266583A (en) * 1992-09-01 1993-11-30 Merck & Co., Inc. Angitotensin II antagonist
DE4308504A1 (en) * 1993-03-18 1994-09-22 Knoll Ag New use of a combination of verapamil and trandolapril
DE4309553A1 (en) * 1993-03-24 1994-09-29 Bayer Ag Process for the preparation of 3R, 5S - (+) - sodium erythro- (E) -7- (4- (4-flurophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl) -3, 5-dihydroxy-hept-6-enoate
US6369103B1 (en) * 1994-01-18 2002-04-09 Bristol-Myers Squibb Company Method for preventing or reducing risk of onset of cardiovascular events employing an HMG CoA reductase inhibitor
ES2079315B1 (en) * 1994-02-24 1996-10-16 Uriach & Cia Sa J NEW IMIDAZOPIRIDINES.
ES2105939B1 (en) * 1994-08-02 1998-07-01 Uriach & Cia Sa J NEW PIRAZOLES WITH ANTAGONIST ACTIVITY OF ANGIOTENSIN II.
EP0808172B1 (en) * 1995-02-10 2003-06-25 G.D. SEARLE & COMPANY Combination of angiotensin converting enzyme inhibitor and aldosterone antagonist for the treatment of ventricular hypertrophy
EP0738510A3 (en) * 1995-04-20 2005-12-21 L'oreal Use of a HMG-CoA reductase inhibitor as an anti-ageing agent and as an anti-acne agent. Composition comprising at least one HMG-CoA reductase inhibitor and at least one active substance with scaling properties.
US5656603A (en) * 1995-05-31 1997-08-12 Loyola University Of Chicago Aminopeptidase P inhibitors and uses thereof
TW442301B (en) * 1995-06-07 2001-06-23 Sanofi Synthelabo Pharmaceutical compositions containing irbesartan
GB2308064A (en) * 1995-10-31 1997-06-18 Merck & Co Inc Treatment of congestive heart failure with a growth hormone secretagogue
AU2252297A (en) * 1996-01-31 1997-08-22 Technology Licensing Co., L.L.C. Method of diagnosis and treatment and related compositions and apparatus
EP0795327A1 (en) * 1996-03-13 1997-09-17 Pfizer Inc. Use of Amlodipine for the treatment and prophylaxis of congestive cardiac failure of non-ischaemic origin
EP0910375B1 (en) * 1996-06-24 2002-05-02 Merck & Co., Inc. A composition of enalapril and losartan
EE9900278A (en) * 1997-01-10 2000-02-15 Merck & Co., Inc. Angiotensin II antagonists for use in the treatment of symptomatic heart failure
US6180660B1 (en) * 1997-08-26 2001-01-30 Merck & Co., Inc. Cholesterol-lowering therapy
DE69830069T3 (en) * 1997-10-17 2012-02-09 Ark Therapeutics Ltd. USE OF INHIBITORS OF THE RENIN-ANGIOTENSIN SYSTEM FOR THE TREATMENT OF HYPOXIA OR REDUCED METABOLIC CHANGE
US6097772A (en) * 1997-11-24 2000-08-01 Ericsson Inc. System and method for detecting speech transmissions in the presence of control signaling
JPH11222439A (en) * 1998-02-03 1999-08-17 Dainippon Pharmaceut Co Ltd Cerebral vasospasm inhibitor
DE69914460T2 (en) * 1998-03-04 2004-10-28 Takeda Chemical Industries, Ltd. PREPARATION WITH DELAYED DELIVERY OF ACTIVE SUBSTANCES FOR AII ANTAGONISTS, THEIR PRODUCTION AND USE
TR200100062T2 (en) * 1998-07-10 2001-06-21 Novartis Ag Anti-hypertensive combination of valsartan and calcium channel blocker
DE19913528A1 (en) * 1998-12-21 2000-06-29 Sanol Arznei Schwarz Gmbh Treatment of cerebrovascular disease, e.g. due to cerebral ischemia, uses low dosage of the angiotensin converting enzyme inhibitor moexipril
WO2000071751A1 (en) * 1999-05-21 2000-11-30 Myriad Genetics, Inc. Diabetes gene
SK2692002A3 (en) * 1999-08-30 2002-07-02 Aventis Pharma Gmbh Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events
GB0020691D0 (en) * 2000-08-22 2000-10-11 Boehringer Ingelheim Pharma Pharmaceutical combination
US20030158090A1 (en) * 2001-07-23 2003-08-21 Ulrik Pedersen-Bjergaard Renin-angiotensin system in diabetes mellitus
US20050065203A1 (en) * 2001-10-17 2005-03-24 Salim Yusuf Method of reducing type 2 diabetes in high risk patients
AU2002364381A1 (en) * 2001-11-23 2003-06-10 Solvay Pharmaceuticals Gmbh Hypertonia treatment during the acute phase of a cerebrovascular accident
ITBO20030050A1 (en) * 2003-02-06 2004-08-07 Ima Spa MACHINE FOR THE TREATMENT OF PHARMACEUTICAL PRODUCTS.

Patent Citations (201)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0079022A2 (en) 1981-11-05 1983-05-18 Hoechst Aktiengesellschaft Derivatives of cis, endo-2-azabicyclo-(3.3.0)-octane-3-carboxylic acid, process for their preparation, medicines containing them and their use
EP0158927A2 (en) 1984-04-12 1985-10-23 Hoechst Aktiengesellschaft Process for the treatment of heart failure
US4722810A (en) 1984-08-16 1988-02-02 E. R. Squibb & Sons, Inc. Enkephalinase inhibitors
US4749688A (en) 1986-06-20 1988-06-07 Schering Corporation Use of neutral metalloendopeptidase inhibitors in the treatment of hypertension
EP0253310A2 (en) 1986-07-11 1988-01-20 E.I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles
US4857520A (en) 1987-02-14 1989-08-15 Hoechst Aktiengesellschaft Fused azepinone and azocinone derivatives, processes for their preparation, agents containing them and their use, and intermediates in their preparation
US4743450A (en) 1987-02-24 1988-05-10 Warner-Lambert Company Stabilized compositions
EP0317878A1 (en) 1987-11-24 1989-05-31 Hoechst Aktiengesellschaft Stabilized pharmaceutical agents, process for preparing them, and stable pharmaceutical preparations
EP0324377A2 (en) 1988-01-07 1989-07-19 E.I. Du Pont De Nemours And Company Angiotensin II receptor blocking imidazoles and combinations thereof with diuretics and NSaids
EP0323841A2 (en) 1988-01-07 1989-07-12 E.I. Du Pont De Nemours And Company Substituted pyrrole, pyrazole and triazole angiotensin II antagonists
EP0399731A1 (en) 1989-05-23 1990-11-28 Zeneca Limited Azaindenes
EP0400974A2 (en) 1989-05-30 1990-12-05 Merck & Co. Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
EP0401030A2 (en) 1989-06-01 1990-12-05 Merck & Co. Inc. Angiotensin II antagonists
EP0403158A2 (en) 1989-06-14 1990-12-19 Smithkline Beecham Corporation Imidazolyl-alkenoic acids
EP0403159A2 (en) 1989-06-14 1990-12-19 Smithkline Beecham Corporation Imidazolyl-alkenoic acids
WO1991000281A2 (en) 1989-06-30 1991-01-10 E.I. Du Pont De Nemours And Company Fused-ring aryl substituted imidazoles
WO1991000277A1 (en) 1989-06-30 1991-01-10 E.I. Du Pont De Nemours And Company Substituted imidazoles
EP0407102A1 (en) 1989-07-03 1991-01-09 Merck & Co. Inc. Substituted imidazo-fused 5-membered ring heterocycles as angiotensin II antagonists
EP0411766A1 (en) 1989-07-03 1991-02-06 Merck & Co. Inc. Substituted quinazolinones as angiotensin II antagonists
EP0407342A2 (en) 1989-07-06 1991-01-09 Ciba-Geigy Ag Pyrimidine derivatives
EP0409332A2 (en) 1989-07-19 1991-01-23 Merck & Co. Inc. Substituted triazoles as angiotensin II antagonists
EP0412594A2 (en) 1989-07-28 1991-02-13 Merck & Co. Inc. Substituted triazolinones, triazolinethiones, and triazolinimines as angiotensin II antagonists
EP0411507A1 (en) 1989-08-02 1991-02-06 Takeda Chemical Industries, Ltd. Pyrazole derivatives, their production and use
EP0412848A2 (en) 1989-08-11 1991-02-13 Zeneca Limited Quinoline derivatives, process for their preparation and their use as medicaments
EP0419048A2 (en) 1989-08-28 1991-03-27 Merck & Co. Inc. Substituted pyrimidinones as angiotensin II antagonists
EP0415886A2 (en) 1989-08-30 1991-03-06 Ciba-Geigy Ag Aza compounds
EP0420237A1 (en) 1989-09-29 1991-04-03 Eisai Co., Ltd. Biphenylmethane derivative, the use of it and pharmacological compositions containing same
EP0424317A2 (en) 1989-10-19 1991-04-24 Ciba-Geigy Ag Pyrimidines
EP0425921A1 (en) 1989-10-24 1991-05-08 Takeda Chemical Industries, Ltd. Benzimidazole derivatives, their production and use
EP0425211A1 (en) 1989-10-25 1991-05-02 Smithkline Beecham Corporation Substituted 5-((tetrazolyl)alkenyl)-imidazoles
EP0426021A1 (en) 1989-10-31 1991-05-08 Fujisawa Pharmaceutical Co., Ltd. Condensed imidazole derivatives and processes for preparation thereof
EP0427463A1 (en) 1989-11-06 1991-05-15 Smithkline Beecham Corporation Substituted N-(imidazolyl)alkyl alanine derivatives
EP0429257A2 (en) 1989-11-17 1991-05-29 Glaxo Group Limited Indole derivatives
EP0454831A1 (en) 1989-11-20 1991-11-06 Ici Plc Diazine derivatives as angiotensin II receptor antagonists.
EP0438869A1 (en) 1989-11-30 1991-07-31 Eli Lilly And Company Improvements in and relating to angiotensin II antagonists
EP0430300A2 (en) 1989-12-01 1991-06-05 Takeda Chemical Industries, Ltd. Xanthine derivatives, their production and use
EP0434249A2 (en) 1989-12-01 1991-06-26 Glaxo Group Limited Benzofuran derivatives
EP0430709A2 (en) 1989-12-01 1991-06-05 Glaxo Group Limited Benzthiophen derivatives
EP0432737A1 (en) 1989-12-11 1991-06-19 G.D. Searle & Co. Cycloheptimidazolone compounds as angiotensin II antagonists for control of hypertension
EP0434038A1 (en) 1989-12-22 1991-06-26 Takeda Chemical Industries, Ltd. Fused imidazole derivatives, their production and use
EP0435827A2 (en) 1989-12-28 1991-07-03 Ciba-Geigy Ag Diaza compounds
EP0437103A2 (en) 1989-12-29 1991-07-17 Smithkline Beecham Corporation Substituted 5-(alkyl)carboxamide imidazoles
WO1991011999A1 (en) 1990-02-13 1991-08-22 Merck & Co., Inc. Angiotensin ii antagonists incorporating a substituted benzyl element
WO1991012002A1 (en) 1990-02-13 1991-08-22 Merck & Co., Inc. Imidazole angiotensin ii antagonists incorporating a substituted benzyl element
WO1991011909A1 (en) 1990-02-13 1991-08-22 Merck & Co., Inc. Triazole angiotensin ii antagonists incorporating a substituted benzyl element
WO1991012001A1 (en) 1990-02-13 1991-08-22 Merck & Co., Inc. Angiotensin ii antagonists incorporating a substituted benzyl element
EP0517812A1 (en) 1990-02-13 1992-12-16 Merck & Co. Inc. Angiotensin ii antagonists incorporating a substituted benzyl element
EP0515535A1 (en) 1990-02-13 1992-12-02 Merck & Co. Inc. Angiotensin ii antagonists incorporating a substituted benzyl element
EP0515546A1 (en) 1990-02-13 1992-12-02 Merck & Co. Inc. Triazole angiotensin ii antagonists incorporating a substituted benzyl element
EP0515548A1 (en) 1990-02-13 1992-12-02 Merck & Co. Inc. Imidazole angiotensin ii antagonists incorporating a substituted benzyl element
EP0515357A1 (en) 1990-02-14 1992-12-02 Siemens Ag METHOD FOR DEMODULATING SECAM-CODED COLOR TELEVISION SIGNALS WITH LINKED CLOCK AND CIRCUIT ARRANGEMENT FOR IMPLEMENTING THE METHOD.
EP0442473A1 (en) 1990-02-15 1991-08-21 Takeda Chemical Industries, Ltd. Pyrimidinedione derivatives, their production and use
EP0443983A1 (en) 1990-02-19 1991-08-28 Ciba-Geigy Ag Acyl compounds
EP0443568A1 (en) 1990-02-22 1991-08-28 Takeda Chemical Industries, Ltd. Fused thiophene derivatives, their production and use
WO1991013063A1 (en) 1990-03-01 1991-09-05 Schering Aktiengesellschaft Berlin Und Bergkamen New benzimidazole derivatives, method for preparing them and their pharmaceutical use
EP0518931A1 (en) 1990-03-05 1992-12-23 Membrane Technology And Research, Inc. Refrigeration process with purge and recovery of refrigerant
EP0445811A2 (en) 1990-03-07 1991-09-11 Takeda Chemical Industries, Ltd. Nitrogen-containing heterocyclic compounds, their production and use
EP0446062A1 (en) 1990-03-09 1991-09-11 Glaxo Group Limited C-Linked pyrazole derivatives
EP0449699A2 (en) 1990-03-19 1991-10-02 Laboratoires Upsa Pyrazole derivatives as angiotensin II-receptor antagonists, process for their preparation and pharmaceutical compositions containing them
EP0454511A1 (en) 1990-03-20 1991-10-30 Sanofi N-substituted heterocycle derivatives, their preparation, compositions containing them
US5223516A (en) 1990-03-22 1993-06-29 E. R. Squibb & Sons, Inc. 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same
WO1991015209A1 (en) 1990-03-30 1991-10-17 Merck & Co., Inc. Substituted pyrimidines, pyrimidinones and pyridopyrimidines
WO1991015479A1 (en) 1990-03-30 1991-10-17 Merck & Co., Inc. Substituted pyrazoles, isoxazoles and isothiazoles
EP0522038A1 (en) 1990-03-30 1993-01-13 Merck & Co. Inc. Substituted pyrimidines, pyrimidinones and pyridopyrimidines
EP0523141A1 (en) 1990-03-30 1993-01-20 Merck & Co. Inc. Substituted pyrazoles, isoxazoles and isothiazoles
EP0450566A1 (en) 1990-04-04 1991-10-09 Hoechst Aktiengesellschaft Substituted azoles, method for their preparation, these containing compositions and their use
WO1991016313A1 (en) 1990-04-13 1991-10-31 Smithkline Beecham Corporation Substituted benzimidazoles
EP0453210A2 (en) 1990-04-19 1991-10-23 Zeneca Limited Pyridine derivatives
EP0459136A1 (en) 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Benzimidazole derivatives, their production and use
US5703110A (en) 1990-04-27 1997-12-30 Takeda Chemical Industries, Ltd. Benzimidazole derivatives, their production and use
EP0459136B1 (en) 1990-04-27 1996-12-27 Takeda Chemical Industries, Ltd. Benzimidazole derivatives, their production and use
US5196444A (en) 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
WO1991017148A1 (en) 1990-05-04 1991-11-14 G.D. Searle & Co. 1h-substituted-1,2,4-triazole compounds for treatment of cardiovascular disorders
EP0456442A1 (en) 1990-05-09 1991-11-13 Zeneca Limited Quinoline derivatives, process for their preparation and their use as medicaments
EP0456510A1 (en) 1990-05-11 1991-11-13 Merck & Co. Inc. Antihypertensive products, a process for their preparation and pharamaceutical compositions containing them
WO1991018888A1 (en) 1990-05-25 1991-12-12 G.D. Searle & Co. N-substituted-1,2,4-triazolone compounds for treatment of cardiovascular disorders
EP0461039A1 (en) 1990-06-08 1991-12-11 Roussel Uclaf Benzimidazole derivatives, process and intermediates for their preparation, their use as medicaments and pharmaceutical compositions containing them
EP0461040A1 (en) 1990-06-08 1991-12-11 Roussel Uclaf Imidazol derivatives, their process for production, intermediates, their application as medicaments and the pharmaceutical compositions containing them
WO1991019715A1 (en) 1990-06-15 1991-12-26 G.D. Searle & Co. 1H-SUBSTITUTED-IMIDAZO[4,5-d]PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS
WO1991019697A1 (en) 1990-06-19 1991-12-26 Meiji Seika Kabushiki Kaisha Pyridine derivative with angiotensin ii antagonism
EP0487745A1 (en) 1990-06-19 1992-06-03 Meiji Seika Kabushiki Kaisha Pyridine derivative with angiotensin ii antagonism
WO1992000067A2 (en) 1990-06-22 1992-01-09 E.I. Du Pont De Nemours And Company Treatment of chronic renal failure with imidazole angiotensin-ii receptor antagonists
WO1992000068A1 (en) 1990-06-28 1992-01-09 Smithkline Beecham Corporation Substituted histidines
EP0465323A1 (en) 1990-07-02 1992-01-08 Laboratoires Upsa Pyrimidin derivatives, angiotensin II receptor antagonists, their process of preparation and pharmaceutical compositions containing them
EP0465368A1 (en) 1990-07-05 1992-01-08 Roussel Uclaf Sulfur derivatives of imidazole, process for their preparation, intermediates, their use as medicaments, and pharmaceutical compositions containing them
WO1992000977A2 (en) 1990-07-13 1992-01-23 E.I. Du Pont De Nemours And Company 4-alkylimidazole derivatives
EP0467207A2 (en) 1990-07-18 1992-01-22 F. Hoffmann-La Roche Ag Purinderivate
EP0467715A1 (en) 1990-07-19 1992-01-22 Merck & Co. Inc. Microbial transformation process for antihypertensive products
EP0468372A2 (en) 1990-07-21 1992-01-29 Hoechst Aktiengesellschaft Substituted azoles, process for their preparation and their use
EP0468470A1 (en) 1990-07-23 1992-01-29 Dr. Karl Thomae GmbH Benzimidazoles, medicaments containing them and process for their preparation
WO1992002510A1 (en) 1990-07-31 1992-02-20 Smithkline Beecham Corporation Substituted [1h-imidazol-5-yl]alkanoic acids
EP0470543A1 (en) 1990-08-10 1992-02-12 Dr. Karl Thomae GmbH Heterocyclic imidazoles, remedies containing them and processes for their preparation
WO1992004335A2 (en) 1990-08-28 1992-03-19 G.D. Searle & Co. Renal-selective biphenylalkyl 1h-substituted-1,2,4-triazole angiotensin ii antagonists for treatment of hypertension
WO1992004343A1 (en) 1990-09-04 1992-03-19 Yamanouchi Pharmaceutical Co., Ltd. Novel tetrahydrobenzazole derivative
EP0475206A2 (en) 1990-09-10 1992-03-18 Abbott Laboratories Angiotensin II receptor antagonists
EP0475898A1 (en) 1990-09-10 1992-03-18 Ciba-Geigy Ag Azacyclic compounds
WO1992005161A1 (en) 1990-09-19 1992-04-02 G.D. Searle & Co. 1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders
EP0480204A1 (en) 1990-09-25 1992-04-15 Fujisawa Pharmaceutical Co., Ltd. Imidazole derivatives, potent and selective antagonists of angiotensin II receptor
WO1992006081A1 (en) 1990-09-28 1992-04-16 Warner-Lambert Company Anilide derivatives with angiotensin ii antagonist properties
EP0481614A1 (en) 1990-10-01 1992-04-22 Merck & Co. Inc. Substituted pyridopyrimidinones and related heterocycles as angiotensin II antagonists
EP0479479A1 (en) 1990-10-01 1992-04-08 Merck & Co. Inc. Imadazole angiotensin II antagonists incorporating acidic functional groups
EP0480659A2 (en) 1990-10-08 1992-04-15 Merck & Co. Inc. Use of Angiotensin-II antagonists for the manufacture of a medicament for the treatment of hyperuricemia
EP0481448A1 (en) 1990-10-16 1992-04-22 E.R. SQUIBB & SONS, INC. Dihydropyrimidine derivatives
EP0481522A1 (en) 1990-10-18 1992-04-22 Merrell Pharmaceuticals Inc. Novel mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
US5430145A (en) 1990-10-18 1995-07-04 Merrell Dow Pharmaceuticals Inc. Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
WO1992007852A1 (en) 1990-10-25 1992-05-14 G.D. Searle & Co. Biphenylalkyl xanthine compounds for treatment of cardiovascular disorders
EP0483683A2 (en) 1990-10-30 1992-05-06 Takeda Chemical Industries, Ltd. Thienoimidazole derivatives, their production and use
EP0488532A1 (en) 1990-10-31 1992-06-03 E.R. Squibb & Sons, Inc. Indole- and benzimidazole-substituted imidazole and benzimidazole derivatives
WO1992007834A1 (en) 1990-10-31 1992-05-14 G.D. Searle & Co. N-substituted imidazol-2-one compounds for treatment of circulatory disorders
EP0485929A1 (en) 1990-11-16 1992-05-20 Hoechst Aktiengesellschaft Substituted azoles, process for their preparation and their application
EP0492105A2 (en) 1990-11-17 1992-07-01 Hoechst Aktiengesellschaft Treatment of cardiac hypertrophy with angiotensin-II-receptor-blockers
EP0487252A1 (en) 1990-11-19 1992-05-27 Zeneca Limited Quinoline and 1,5-Naphthyridine derivatives, process and intermediates for their preparation and pharmaceutical compositions containing them
WO1992009600A1 (en) 1990-11-29 1992-06-11 Glaxo Group Limited Benzofuran and benzthiophene derivatives
WO1992009278A1 (en) 1990-11-30 1992-06-11 Smithkline Beecham Corporation Substituted 5-aryl imidazoles
EP0490587A1 (en) 1990-12-07 1992-06-17 Merck & Co. Inc. Substituted pyrazolopyrimidines and imidazopyridazines as angiotensin II antagonists
EP0490820A2 (en) 1990-12-14 1992-06-17 Ciba-Geigy Ag Biphenylyl compounds
WO1992010189A1 (en) 1990-12-14 1992-06-25 Smithkline Beecham Corporation Imidazolyl-alkenoic acids
WO1992011255A1 (en) 1990-12-20 1992-07-09 G.D. Searle & Co. N-SUBSTITUTED N-(α-TRIAZOLYL-TOLUYL)PYRROLE COMPOUNDS FOR TREATMENT OF CIRCULATORY DISORDERS
EP0503162A1 (en) 1991-01-04 1992-09-16 Hoechst Aktiengesellschaft Azole derivatives, process for their preparation and their application
EP0497150A1 (en) 1991-01-30 1992-08-05 American Cyanamid Company Angiotensin II receptor blocking 2,3,6-substituted quinazolones
EP0497516A1 (en) 1991-01-30 1992-08-05 Merck & Co. Inc. Substituted pyrrolo-fused 6-membered heterocycles as angiotensin II antagonists
EP0497121A1 (en) 1991-01-31 1992-08-05 Chemisch Pharmazeutische Forschungsgesellschaft m.b.H. Tetrazole derivatives, process for their production and their application
EP0502314A1 (en) 1991-02-06 1992-09-09 Dr. Karl Thomae GmbH Benzimidazol, medicaments containing them and process for their preparation
EP0498721A1 (en) 1991-02-07 1992-08-12 Roussel Uclaf N-substituted quinoline derivatives, process for their preparation, intermediates obtained, their use as pharmaceuticals and pharmaceutical compositions containing them
EP0498722A1 (en) 1991-02-07 1992-08-12 Roussel Uclaf Bicyclic nitrogen compounds, their preparation, intermediates obtained, their use as pharmaceuticals and pharmaceutical compositions containing them
EP0498723A1 (en) 1991-02-07 1992-08-12 Roussel Uclaf Nitrogen containing bicycle compounds, method for their preparation, their use as pharmaceutical and compositions containing them
EP0499415A1 (en) 1991-02-11 1992-08-19 Zeneca Limited Pyridine and quinoline derivatives, processes for their manufacture and their use as angiotensin II antagonists
EP0499416A2 (en) 1991-02-11 1992-08-19 Zeneca Limited Pyridine compounds as angiotensin II antagonists, processes for their preparation and pharmaceutical compositions containing them
EP0499414A2 (en) 1991-02-11 1992-08-19 Zeneca Limited Pyridine derivatives as angiotensin II antagonists, processes for their preparation and pharmaceutical compositions containing them
WO1992014714A1 (en) 1991-02-16 1992-09-03 Fisons Plc Substituted pyridinones and pyrimidinones as angiotensin ii antagonists
EP0500297A1 (en) 1991-02-16 1992-08-26 FISONS plc Substituted pyridinones and pyrimidinones as angiotensin II antagonists
EP0500409A1 (en) 1991-02-20 1992-08-26 Synthelabo 4-Pyrimidinone derivatives, their preparation and their application in therapy
EP0503785A1 (en) 1991-02-21 1992-09-16 Sankyo Company Limited 1-Biphenylimidazole derivatives, their preparation and their therapeutic use
EP0501269A1 (en) 1991-02-26 1992-09-02 E.R. SQUIBB & SONS, INC. Imidazole and benzimidazole derivatives
EP0501892A1 (en) 1991-03-01 1992-09-02 Sanofi Diazotized heterocyclic derivatives N-substituted by a biphenylmethyl group, their preparation and pharmaceutical compositions containing them
EP0502725A2 (en) 1991-03-06 1992-09-09 Merck & Co. Inc. Substituted fused pyrimidinones
EP0502575A1 (en) 1991-03-06 1992-09-09 Merck & Co. Inc. Substituted 1-(2H)-isoquinolinones
EP0503838A2 (en) 1991-03-08 1992-09-16 Merck & Co. Inc. Heterocyclic compounds bearing acidic functional groups as angiotensin II antagonists
EP0505098A1 (en) 1991-03-19 1992-09-23 Merck & Co. Inc. Imidazole derivatives bearing acidic functional groups as angiotensin II antagonists
EP0504888A1 (en) 1991-03-21 1992-09-23 G.D. Searle & Co. 5-Arylheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders
WO1992016523A1 (en) 1991-03-21 1992-10-01 G.D. Searle & Co. 5-arylheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders
EP0505111A2 (en) 1991-03-22 1992-09-23 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted imidazo (1,2-b)(1,2,4) triazole
EP0505954A1 (en) 1991-03-25 1992-09-30 Glaxo Group Limited N-Imidazolylmethyl benzofuran derivatives as inhibitors of angiotensin II activity
WO1992016552A1 (en) 1991-03-25 1992-10-01 Glaxo Group Limited 1-imidazolgemethyl benzofuran derivatives as inhibitors of angiotensin ii activity
EP0510813A1 (en) 1991-03-25 1992-10-28 Merck & Co. Inc. Angiotensin II antagonists incorporating a nitrogen containing six membered ring heterocycle
EP0513979A1 (en) 1991-03-26 1992-11-19 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted thiophene or furan
EP0505893A1 (en) 1991-03-27 1992-09-30 MERCK PATENT GmbH Imidazopyridines
EP0508393A1 (en) 1991-04-05 1992-10-14 G.D. Searle & Co. N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders
EP0507594A1 (en) 1991-04-05 1992-10-07 Merck & Co. Inc. Substituted quinolines as angiotensin II antagonists
WO1992017469A2 (en) 1991-04-05 1992-10-15 G.D. Searle & Co. N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders
EP0508723A1 (en) 1991-04-08 1992-10-14 Merck & Co. Inc. Angiotensin II antagonists incorporating an indole or dihydroindole
EP0508445A1 (en) 1991-04-12 1992-10-14 G.D. Searle & Co. 1-Arylheteroarylalkyl substituted-1H-1,2,4-triazole compounds for treatment of circulatory disorders
WO1992018092A2 (en) 1991-04-12 1992-10-29 G.D. Searle & Co. 1-arylheteroarylalkyl substituted-1h-1,2,4-triazole compounds for treatment of circulatory disorders
EP0518033A1 (en) 1991-04-16 1992-12-16 Takeda Chemical Industries, Ltd. Fused heterocyclic compounds, their production and use
EP0513533A2 (en) 1991-04-26 1992-11-19 Bayer Ag Heterocyclic substituted phenylacetic-acid derivatives, process for their preparation and their pharmaceutical application
EP0510812A1 (en) 1991-04-26 1992-10-28 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted thiophene or furan
EP0511767A1 (en) 1991-04-29 1992-11-04 Merck & Co. Inc. Tablets containing compound DUP753
EP0511791A2 (en) 1991-04-30 1992-11-04 Zeneca Limited Pyrrolopyridine derivatives as Angiotensin inhibitors
EP0512676A1 (en) 1991-05-07 1992-11-11 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted benzyl element
EP0512675A1 (en) 1991-05-07 1992-11-11 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted thiophene or furan
WO1992019211A2 (en) 1991-05-08 1992-11-12 The Upjohn Company Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same
WO1992020687A1 (en) 1991-05-10 1992-11-26 Merck & Co., Inc. Substituted pyrimidinones bearing acidic functional groups as angiotensin ii antagonists
WO1992020660A1 (en) 1991-05-10 1992-11-26 Merck & Co., Inc. Substituted 1-(2h)-isoquinolinones bearing acidic functional groups as angiotensin ii antagonists
EP0512870A1 (en) 1991-05-10 1992-11-11 Merck & Co. Inc. Substituted quinazolinones bearing acidic functional groups as angiotensin II antagonists
WO1992020651A2 (en) 1991-05-15 1992-11-26 Smithkline Beecham Corporation N-(heteroaryl)-imidazolyl-alkenoic acids
EP0514197A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited Anti-hypertensive benzofuran derivatives substituted by N-imidazolyl-methyl groups which are condensed with optionally nitrogen containing, six-membered rings
EP0514217A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited Antihypertensive benzofuran derivatives carrying 4-pyrazolylmethyl substituents
EP0514193A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited N-linked imidazolyl-methyl benzofuran derivatives with antihypotensive activity
EP0514198A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited 1H-Imidazol-1-yl-methyl benzofuran derivatives with the imidazolyl moiety being substituted by a cycloalkyl group
EP0514192A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited Antihypertensive benzofuran derivatives, substituted by varied N-pyrimidinyl- or N-imidazolyl-methyl groups
EP0514216A1 (en) 1991-05-16 1992-11-19 Glaxo Group Limited Antihypotensive benzofuran derivatives with N-linked 1H-imidazolyl-methyl-5-carboxamide substituents
EP0515265A1 (en) 1991-05-23 1992-11-25 Roussel Uclaf Pyrimidin derivates, process for their preparation, the obtained intermediates, their use as medicines and the pharmaceutical compositions containing them
EP0516392A2 (en) 1991-05-31 1992-12-02 Zeneca Limited Naphthyridine derivatives as angiotensin II inhibitors
WO1992021666A1 (en) 1991-05-31 1992-12-10 Laboratoires Upsa Angiotensin ii receptor antagonist thiazole devivatives
EP0517357A1 (en) 1991-06-05 1992-12-09 Merck & Co. Inc. Angiotensin II antagonists incorporating a substituted indole or dihydroindole
WO1992022533A1 (en) 1991-06-14 1992-12-23 The Upjohn Company 4-aminoquinolines and pharmaceutical compositions thereof
WO1993000341A1 (en) 1991-06-21 1993-01-07 Warner-Lambert Company 4-(1-h-pyrrol-1-yl)imidazoles with angiotensin ii antagonist activity
EP0520723A1 (en) 1991-06-25 1992-12-30 Imperial Chemical Industries Plc Angiotensin II antagonists
EP0520724A1 (en) 1991-06-25 1992-12-30 Zeneca Limited Angiotensin II antagonists
EP0520423A2 (en) 1991-06-27 1992-12-30 Takeda Chemical Industries, Ltd. Heterocyclic compounds, their production and use as angiotensin II antagonists
EP0526001A1 (en) 1991-07-03 1993-02-03 Merck & Co. Inc. Substituted triazolinones
WO1993001177A1 (en) 1991-07-03 1993-01-21 Merck & Co., Inc. Substituted triazolinones
EP0521768A1 (en) 1991-07-05 1993-01-07 Laboratoires Upsa Thiazolopyrimidine derivatives as angiotensin II-receptor antagonists: processes for their preparation and pharmaceutical compositions containing them
WO1993003033A1 (en) 1991-07-26 1993-02-18 G. D. Searle & Co. CARBONATE-SUBSTITUTED IMIDAZO[4,5-d] PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS
WO1993003018A1 (en) 1991-08-02 1993-02-18 Istituto Luso Farmaco D'italia S.P.A. Compounds having angiotensine ii antagonistic activity
WO1993003040A1 (en) 1991-08-05 1993-02-18 Taisho Pharmaceutical Co., Ltd. Thienopyrimidin-4-one derivative
US5225401A (en) 1991-08-12 1993-07-06 E. R. Squibb & Sons, Inc. Treatment of congestive heart failure
EP0527534A1 (en) 1991-08-13 1993-02-17 Merck & Co. Inc. Quinoline and azaquinoline angiotensin II antagonists
EP0528762A1 (en) 1991-08-15 1993-02-24 Ciba-Geigy Ag N-acyl-N-heterocyclyl- or naphthyl-alkyl amino acids as angiotensin II antagonists
EP0534263A1 (en) 1991-09-20 1993-03-31 L.G.L. ELECTRONICS S.p.A. Self-adjusting thread braking device for weft feeder units
EP0534492A2 (en) 1991-09-27 1993-03-31 Merrell Pharmaceuticals Inc. Carboxyalkyl substituted inhibitors of enkephalinase and ACE
EP0534396A2 (en) 1991-09-27 1993-03-31 Merrell Pharmaceuticals Inc. 2-Substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ace
US5366973A (en) 1992-05-15 1994-11-22 Merrell Dow Pharmaceuticals Inc. Mercaptoacetylamido pyridazo [1,2]pyridazine, pyrazolo[1,2]pyridazine pyrazolo[1,2]pyridazine, pyridazol[1,2-a][1,2]diazepine and pyrazolol[1,2-a][1,2]diazepine
US5552397A (en) 1992-05-18 1996-09-03 E. R. Squibb & Sons, Inc. Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase
US5504080A (en) 1992-10-28 1996-04-02 Bristol-Myers Squibb Co. Benzo-fused lactams
US5679671A (en) 1993-06-11 1997-10-21 Eisai Co., Ltd. Amino acid derivative
EP0671172A1 (en) 1993-06-11 1995-09-13 Eisai Co., Ltd. Amino acid derivative
US5508272A (en) 1993-06-15 1996-04-16 Bristol-Myers Squibb Company Compounds containing a fused bicycle ring and processes therefor
US5362727A (en) 1993-07-26 1994-11-08 Bristol-Myers Squibb Substituted azepino[2,1-a]isoquinoline compounds
US5525723A (en) 1993-11-18 1996-06-11 Bristol-Myers Squibb Co. Compounds containing a fused multiple ring lactam
US5612359A (en) 1994-08-26 1997-03-18 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides

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